Interleukin-6 family signaling (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Interleukin-6 family signaling" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">The interleukin-6 (IL6) family of cytokines includes IL6, IL11, IL27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 and 2 (CT-1) and cardiotrophin-like cytokine (CLC) (Heinrich et al. 2003, Pflanz et al. 2002). The latest addition to this family is IL31, discovered in 2004 (Dillon et al. 2004). The family is defined largely by the shared use of the common signal transducing receptor Interleukin-6 receptor subunit beta (IL6ST, gp130). The IL31 receptor uniquely does not include this subunit, instead it uses the related IL31RA. The members of the IL6 family share very low sequence homology but are structurally highly related, forming anti-parallel four-helix bundles with a characteristic “up-up-down-downâ€� topology (Rozwarski et al. 1994, Cornelissen et al. 2012).&lt;br&gt;&lt;br&gt;Although each member of the IL6 family signals through a distinct receptor complex, their underlying signaling mechanisms are similar. Assembly of the receptor complex is followed by activation of receptor-associated Janus kinases (JAKs), believed to be constitutively associated with the receptor subunits.Activation of JAKs initiates downstream cytoplasmic signaling cascades that involve recruitment and phosphorylation of transcription factors of the Signal transducer and activator of transcription (STAT) family, which dimerize and translocate to the nucleus where they bind enhancer elements of target genes leading to transcriptional activation (Nakashima &amp; Taga 1998).&lt;br&gt;&lt;br&gt;Negative regulators of IL6 signaling include Suppressor of cytokine signals (SOCS) family members and PTPN11 (SHP-2).&lt;br&gt;&lt;br&gt;IL6 is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. &lt;br&gt;&lt;br&gt;IL6 and IL11 bind their corresponding specific receptors IL6R and IL11R respectively, resulting in dimeric complexes that subsequently associate with IL6ST, leading to IL6ST homodimer formation (in a hexameric or higher order complex) and signal initiation. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL6 activities&lt;br&gt;&lt;br&gt;LIF, CNTF, OSM, CTF1, CRLF1 and CLCF1 signal via IL6ST:LIFR heterodimeric receptor complexes (Taga &amp; Kishimoto 1997, Mousa &amp; Bakhiet 2013). OSM signals via a receptor complex consisting of IL6ST and OSMR. These cytokines play important roles in the regulation of complex cellular processes such as gene activation, proliferation and differentiation (Heinrich et al. 1998). &lt;br&gt;&lt;br&gt;Antibodies have been developed to inhibit IL6 activity for the treatment of inflammatory diseases (Kopf et al. 2010). View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=6783589 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 6783589</Comment> <Comment Source="Reactome-version">Reactome version: 63</Comment> <Comment Source="Reactome Author">Reactome Author: Garapati, Phani Vijay</Comment> <BiopaxRef>ddb</BiopaxRef> <BiopaxRef>cc3</BiopaxRef> <BiopaxRef>d25</BiopaxRef> <BiopaxRef>b31</BiopaxRef> <BiopaxRef>dcb</BiopaxRef> <BiopaxRef>d0c</BiopaxRef> <BiopaxRef>cf3</BiopaxRef> <BiopaxRef>fa3</BiopaxRef> <BiopaxRef>cc2</BiopaxRef> <Attribute Key="reactome_id" Value="6783589" /> <Graphics BoardWidth="2719.0" BoardHeight="2083.0" /> <DataNode TextLabel="Tyrosine&#xA;phosphorylated IL6&#xA;receptor&#xA;hexamer:Activated&#xA;JAKs:SOCS3" GraphId="a0051" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2007.0" CenterY="227.0" Width="124.0" Height="78.0" ZOrder="32768" FontSize="10" 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TextLabel="p-Y1034-JAK1 " GraphId="e37b8" Type="Protein" GroupRef="b6676"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112524" /> <Attribute Key="copies_num" Value="11" /> <Graphics CenterX="520.0" CenterY="1503.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P23458" /> </DataNode> <DataNode TextLabel="STAT1 " GraphId="e3b38" Type="Protein" GroupRef="eaccb"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112576" /> <Attribute Key="copies_num" Value="72" /> <Graphics CenterX="380.0" CenterY="2043.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P42224" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="e429e" Type="Protein" GroupRef="c341e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1067654" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1503.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="CNTF " GraphId="e43f5" Type="Protein" GroupRef="dd408"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-6783659" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1923.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P26441" /> </DataNode> <DataNode TextLabel="JAKs:LIFR" GraphId="e4534" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="128.0" CenterY="354.0" Width="64.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-6784198" /> </DataNode> <DataNode TextLabel="IL6R " GraphId="e5548" Type="Protein" GroupRef="b6676"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1112524" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="520.0" CenterY="1463.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08887" /> </DataNode> <DataNode TextLabel="CNTF:CNTFR,CRLF1:CLCF1:CNTFR" GraphId="e5ba0" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="135.0" CenterY="647.0" Width="126.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-6783659" /> </DataNode> <DataNode TextLabel="LIF " GraphId="e66f9" Type="Protein" GroupRef="d4c33"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-6783699" /> <Attribute Key="copies_num" Value="1" /> <Graphics 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Type="Protein" GroupRef="b8028"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112753" /> <Attribute Key="copies_num" Value="152" /> <Graphics CenterX="660.0" CenterY="2023.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q06124" /> </DataNode> <DataNode TextLabel="TYK2 " GraphId="e6d46" Type="Protein" GroupRef="a1fa5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112588" /> <Attribute Key="copies_num" Value="68" /> <Graphics CenterX="240.0" CenterY="1863.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P29597" /> </DataNode> <DataNode TextLabel="IL6R " GraphId="e7d9d" Type="Protein" GroupRef="f788a"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1112594" /> <Attribute Key="copies_num" Value="5" /> 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<DataNode TextLabel="Tyrosine&#xA;phosphorylated&#xA;IL6&#xA;receptor&#xA;hexamer:Activated&#xA;JAKs:Tyrosine/serine phosphorylated STAT1/3" GraphId="e9653" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="2595.5" CenterY="817.0" Width="175.0" Height="70.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1112759" /> </DataNode> <DataNode TextLabel="STAT3 " GraphId="e971b" Type="Protein" GroupRef="eaccb"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112576" /> <Attribute Key="copies_num" Value="72" /> <Graphics CenterX="380.0" CenterY="2023.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P40763" /> </DataNode> <DataNode TextLabel="CNTFR " GraphId="ea144" Type="Protein" GroupRef="a0b3f"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-6783596" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1823.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P26992" /> </DataNode> <DataNode TextLabel="ATP" GraphId="ea70e" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1593.0" CenterY="305.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15422" /> </DataNode> <DataNode TextLabel="IL6 " GraphId="ea757" Type="Protein" GroupRef="f9aa6"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1067687" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1623.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P05231" /> </DataNode> <DataNode TextLabel="p-Y705-STAT3 " GraphId="ec972" Type="Protein" GroupRef="e596e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-1112574" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="660.0" CenterY="1623.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P40763" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="eccb8" Type="Protein" GroupRef="c8158"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1067690" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1523.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="IL6R " GraphId="ed073" Type="Protein" GroupRef="f9be2"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1112744" /> 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/> <Graphics CenterX="520.0" CenterY="1683.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08887" /> </DataNode> <DataNode TextLabel="STAT3 " GraphId="f2bd2" Type="Protein" GroupRef="e3b30"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112559" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1803.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P40763" /> </DataNode> <DataNode TextLabel="OSM:OSMR,LIFR" GraphId="f310a" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="129.0" CenterY="1009.0" Width="102.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-6783585" /> </DataNode> <DataNode TextLabel="p-Y1054-TYK2 " GraphId="f3566" Type="Protein" 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FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P40763" /> </DataNode> <DataNode TextLabel="JAKs:OSMR" GraphId="f4d58" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="136.5" CenterY="1132.0" Width="75.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-6784202" /> </DataNode> <DataNode TextLabel="p-Y1034-JAK1 " GraphId="f5323" Type="Protein" GroupRef="b8028"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1112753" /> <Attribute Key="copies_num" Value="11" /> <Graphics CenterX="660.0" CenterY="1943.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P23458" /> </DataNode> <DataNode TextLabel="ADP" GraphId="f5527" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="2463.5" CenterY="804.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16761" /> </DataNode> <DataNode TextLabel="LIFR " GraphId="f637b" Type="Protein" GroupRef="ba8c1"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-6783544" /> <Attribute Key="copies_num" Value="42" /> <Graphics CenterX="940.0" CenterY="1923.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P42702" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="f68a4" Type="Protein" GroupRef="f7745"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-6783658" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="940.0" CenterY="1543.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="LIFR " 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GroupRef="eaccb"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1112576" /> <Attribute Key="copies_num" Value="72" /> <Graphics CenterX="380.0" CenterY="2003.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08887-2" /> </DataNode> <Interaction GraphId="a195d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1370.0" Y="244.0" GraphRef="ff68f" RelX="-0.009900990099009901" RelY="1.0" /> <Point X="1402.0" Y="268.0" GraphRef="c1f48" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112514" /> </Interaction> <Interaction GraphId="a1d29"> <Comment Source="Reactome">Interleukin-11 receptor alpha subunit (IL11RA) binds interleukin-11 (IL11) with low affinity but for high affinity binding and signaling must associate with interleukin-6 receptor beta subunit (IL6ST, gp130).</Comment> <BiopaxRef>e67</BiopaxRef> <BiopaxRef>d9f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="888.0" Y="125.0" /> <Point X="1088.0" Y="193.0" /> <Anchor Position="0.0" Shape="None" GraphId="b90ac" /> <Anchor Position="0.99" Shape="None" GraphId="e22a6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449976" /> </Interaction> <Interaction GraphId="a2915"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="39.0" Y="343.0" GraphRef="ef651" RelX="0.92" RelY="0.0" /> <Point X="63.0" Y="362.0" GraphRef="d9c5b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783681" /> </Interaction> <Interaction GraphId="a48fc"> <Comment Source="Reactome">Suppressor of cytokine signaling protein 3 (SOCS3) binds to the same IL6ST (gp130) phosphotyrosine (Tyr-759) as PTPN11 (SHP2) (Schmitz et al. 2000) though they appear to suppress Interleukin-6 (IL6) signaling by independent mechanisms (Lehmann et al. 2003). Members of the SOCS family (CIS and SOCS1-7) have an N-terminal SH2 domain preceded by an extended SH2 domain (ESS) and kinase inhibitory region (KIR) (Hilton et al. 1998). The related SOCS1 associates with JAKs via its KIR and SH2 domains (Narazaki et al. 1998, Yasukawa et al. 1999) leading to inhibition of JAK signaling and kinase activity. SOCS3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS1 and SOCS3 inhibit signaling in different ways (Nicholson et al. 1999), but it is possible that SOCS3's inhibitory actions require binding to both activated receptor gp130 Tyr-759 and the associated JAK for maximal inhibition (Greenhalgh &amp; Hilton 2001). Socs3 deficiency results in prolonged STAT1/3 activation after IL6 but not interferon-gamma (IFNG) stimulation suggesting that SOCS3 has a role in preventing IFNG-like responses in cells stimulated by IL6 (Croker et al. 2003).</Comment> <BiopaxRef>f1f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1884.0" Y="248.0" /> <Point X="1942.0" Y="240.0" /> <Anchor Position="0.0" Shape="None" GraphId="f9903" /> <Anchor Position="0.99" Shape="None" GraphId="b662b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112755" /> </Interaction> <Interaction GraphId="a7b73"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2561.0" Y="739.0" GraphRef="d564d" RelX="0.0" RelY="0.5800000000000409" /> <Point X="2595.0" Y="782.0" GraphRef="e9653" RelX="-0.005714285714285714" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112727" /> </Interaction> <Interaction GraphId="a7c7e"> <Comment Source="Reactome">STAT1 binds to IL6ST (gp130) via phosphotyrosine residues 905 and 915 within two YXPD recognition motifs. STAT3 can be recruited to these sites and to two additional sites around Y767 and Y814 that have less restricted sequence recognition requirements (YXXQ) (Gerhartz et al. 1996). After receptor binding, STATs are phosphorylated on a single tyrosine residue by JAKs (Hemmann et al. 1996).</Comment> <BiopaxRef>b57</BiopaxRef> <BiopaxRef>e29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1968.0" Y="397.0" /> <Point X="2519.0" Y="404.0" /> <Anchor Position="0.0" Shape="None" GraphId="c1ff7" /> <Anchor Position="0.99" Shape="None" GraphId="c8138" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112565" /> </Interaction> <Interaction GraphId="a8842"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1088.0" Y="193.0" GraphRef="e22a6" RelX="2.0" RelY="0.6800000000000068" /> <Point X="1103.0" Y="196.0" GraphRef="e1796" RelX="-0.014084507042253521" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449976" /> </Interaction> <Interaction GraphId="a8c1b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="556.0" Y="218.0" GraphRef="aa10a" RelX="0.9764705882352941" RelY="-0.02702702702702703" /> <Point X="692.0" Y="143.0" GraphRef="e798c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067651" /> </Interaction> <Interaction GraphId="a9fe3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1712.0" Y="817.0" GraphRef="c1e18" RelX="0.5499999999999545" RelY="0.0" /> <Point X="1742.0" Y="856.0" GraphRef="d14f5" RelX="-1.0" RelY="-0.012658227848101266" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112703" /> </Interaction> <Interaction GraphId="aa294"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2545.0" Y="551.0" GraphRef="f50f4" RelX="0.0" RelY="0.6599999999999682" /> <Point X="2486.0" Y="564.0" GraphRef="b0724" RelX="0.9487179487179487" RelY="-0.02702702702702703" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="aabda"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1853.0" Y="226.0" GraphRef="dec65" RelX="1.0" RelY="0.0" /> <Point X="1884.0" Y="248.0" GraphRef="f9903" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112755" /> </Interaction> <Interaction GraphId="aae24"> <Comment Source="Reactome">There are three contact sites between IL-6, IL-6R and gp130, named site I, II and III. Site I and II correspond to the respective sites of the growth hormone receptor complex whereas site III is only found in receptor complexes with at least three subunits. Various models of the IL-6 receptor complex have been proposed (Scheller &amp; Rose-John 2006), but crystallographic data suggests the assembly of a hexameric complex containing two IL-6, two IL-6RA and two gp130 subunits. It has been argued that the minimal signalling complex is one IL6:IL6R complex bound to two gp130 proteins (Grotzinger et al. 1999). The quaternary structures of other IL-6/IL-12 family signaling complexes suggest they have a similar topology (Boulanger et al. 2003). IL-6 binding is achieved by the cytokine-binding and the immunglobulin-like domains (Boulanger et al. 2003). The gp130 fibronectin-like domains are thought to position the transmembrane domains of the paired gp130 receptor complexes in close proximity and thereby induce signaling (Skiniotis et al. 2005). Forced dimerization of gp130 with itself or the related Interleukin-27 receptor subunit alpha (WSX-1), Leukemia inhibitory factor receptor or Oncostatin M receptors led to constitutive, ligand-independent STAT1 and/or STAT3 activation and ERK1/2 phosphorylation, suggesting that all heterodimeric gp130-type receptor complexes are activated by a similar mechanism in which close juxtaposition of the intracellular receptor domains is sufficient for signal induction (Suthaus et al. 2010).</Comment> <BiopaxRef>f55</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1272.0" Y="199.0" /> <Point X="1357.0" Y="203.0" /> <Anchor Position="0.0" Shape="None" GraphId="d6a77" /> <Anchor Position="0.99" Shape="None" GraphId="cde0b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067659" /> </Interaction> <Interaction GraphId="aafc2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1241.0" Y="205.0" GraphRef="fe5b2" RelX="0.0" RelY="-1.0" /> <Point X="1272.0" Y="199.0" GraphRef="d6a77" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067659" /> </Interaction> <Interaction GraphId="aca03"> <Comment Source="Reactome">In addition to tyrosine phosphorylation, STAT1 and STAT3 are phosphorylated at serine-727, which contributes to maximal transcriptional activity (Wen &amp; Darnell 1997, Shen et al. 2004). Though several candidates exist, including Protein kinase C delta (Jain et al. 1999), the kinase responsible for Interleukin-6 regulation of STAT serine phosphorylation is unknown (Jain et al. 1999, Abe et al. 2001, Chung et al. 1997) and the significance of serine phosphorylation is unclear (Decker &amp; Kovarik 2000). STAT3 modifed by serine phosphorylation augments oxidative phosphorylation in mitochondria and supported cellular transformation by oncogenic Ras (Reich 2009).</Comment> <BiopaxRef>a08</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2561.0" Y="681.0" /> <Point X="2561.0" Y="739.0" /> <Anchor Position="0.0" Shape="None" GraphId="a1dcd" /> <Anchor Position="0.99" Shape="None" GraphId="d564d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112727" /> </Interaction> <Interaction GraphId="adb89"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1712.0" Y="817.0" GraphRef="c1e18" RelX="0.5499999999999545" RelY="0.0" /> <Point X="1747.0" Y="770.0" GraphRef="b65f5" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112703" /> </Interaction> <Interaction GraphId="ade22"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="191.0" Y="797.0" GraphRef="dd9af" RelX="0.9826086956521739" RelY="0.0" /> <Point X="361.0" Y="864.0" GraphRef="b323a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783524" /> </Interaction> <Interaction GraphId="ae2dd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1357.0" Y="203.0" GraphRef="cde0b" RelX="0.849999999999909" RelY="0.03999999999999204" /> <Point X="1370.0" Y="206.0" GraphRef="ff68f" RelX="-0.009900990099009901" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067659" /> </Interaction> <Interaction GraphId="af0cf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="150.0" Y="1215.0" GraphRef="a4788" RelX="1.0" RelY="0.0" /> <Point X="398.0" Y="983.0" GraphRef="fbcfb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784204" /> </Interaction> <Interaction GraphId="afaf5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="153.0" Y="1118.0" GraphRef="fd733" RelX="-2.450000000000017" RelY="1.349999999999909" /> <Point X="136.0" Y="1121.0" GraphRef="f4d58" RelX="-0.013333333333333334" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784204" /> </Interaction> <Interaction GraphId="b03f7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2043.0" Y="664.0" GraphRef="d41c8" RelX="0.0" RelY="1.0" /> <Point X="2043.0" Y="670.0" GraphRef="a5ec2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112538" /> </Interaction> <Interaction GraphId="b049e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="728.0" Y="82.0" GraphRef="b8fa1" RelX="-0.008403361344537815" RelY="0.9259259259259259" /> <Point X="731.0" Y="143.0" GraphRef="ae0f2" RelX="11.5" RelY="-29.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067651" /> </Interaction> <Interaction GraphId="b07e3"> <Comment Source="Reactome">Cardiotrophin-like cytokine factor 1 (CLCF1 also referred as NNT1 or BSF3) binds to the tripartite CNTFR complex and activates Jak-STAT, MAPK and PI3/Akt signaling pathways in various cell systems. Function of CLCF1 includes neurotrophic and B cell stimulatory effects, as well as neuroimmunoendocrine modulation of corticotroph function. Cellular secretion of CLCF1 requires heteromeric complex formation with other IL-6 family member cytokine receptor-like factor 1 (CRLF1 also called CLF1). It is a secreted receptor belonging to the interleukin-6 family of cytokines. This heteromeric CRLF1:CLCF1 is a stable sectreted complex that acts as a second ligand for ciliary neurotrophic factor receptor (CNTFR) tripartite receptor complex (Elson et al. 2000, Vlotides et al. 2004).</Comment> <BiopaxRef>ffb</BiopaxRef> <BiopaxRef>cd4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2348.0" Y="189.0" /> <Point X="2381.0" Y="205.0" /> <Anchor Position="0.0" Shape="None" GraphId="de8d7" /> <Anchor Position="0.99" Shape="None" GraphId="be71b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783670" /> </Interaction> <Interaction GraphId="b0dd0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="160.0" Y="354.0" GraphRef="e4534" RelX="1.0" RelY="0.0" /> <Point X="266.0" Y="699.0" GraphRef="c28d1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696482" /> </Interaction> <Interaction GraphId="b27a4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2149.0" Y="174.0" GraphRef="d3dcd" RelX="0.9487179487179487" RelY="0.0" /> <Point X="2169.0" Y="192.0" GraphRef="ad8c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696491" /> </Interaction> <Interaction GraphId="b2ccd"> <Comment Source="Reactome">Following phosphorylation, STATs are released from the receptor.</Comment> <BiopaxRef>cd7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2496.0" Y="608.0" /> <Point X="1820.0" Y="475.0" /> <Anchor Position="0.0" Shape="None" GraphId="d2d46" /> <Anchor Position="0.99" Shape="None" GraphId="b0817" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112604" /> </Interaction> <Interaction GraphId="b33b0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2584.0" Y="444.0" GraphRef="cfebb" RelX="0.0" RelY="1.0" /> <Point X="2545.0" Y="522.0" GraphRef="dc1e4" RelX="0.0" RelY="4.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="b3483"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1577.0" Y="247.0" GraphRef="edcbe" RelX="0.0" RelY="1.0" /> <Point X="1618.0" Y="269.0" GraphRef="ea160" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112510" /> </Interaction> <Interaction GraphId="b365b"> <Comment Source="Reactome">STATs can form dimers in the unphosphorylated state but only phosphorylated dimers are in the correct conformation to to bind consensus DNA sequences of target genes in the nucleus (Riech &amp; Liu 2006).</Comment> <BiopaxRef>cd7</BiopaxRef> <BiopaxRef>e0d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2043.0" Y="670.0" /> <Point X="2044.0" Y="751.0" /> <Anchor Position="0.0" Shape="None" GraphId="a5ec2" /> <Anchor Position="0.99" Shape="None" GraphId="cad26" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112538" /> </Interaction> <Interaction GraphId="b57c0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="974.0" Y="159.0" GraphRef="af6eb" RelX="-1.0" RelY="0.0" /> <Point X="959.0" Y="184.0" GraphRef="ccfed" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449829" /> </Interaction> <Interaction GraphId="b7343"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="475.0" GraphRef="b0817" RelX="-6.759999999999991" RelY="-1.330000000000041" /> <Point X="1791.0" Y="258.0" GraphRef="dec65" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112604" /> </Interaction> <Interaction GraphId="b76e1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="669.0" Y="1268.0" GraphRef="d0836" RelX="2.4600000000000364" RelY="-1.0199999999999818" /> <Point X="682.0" Y="1265.0" GraphRef="b8f2e" RelX="-0.008695652173913044" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448660" /> </Interaction> <Interaction GraphId="b77e2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="96.0" Y="354.0" GraphRef="e4534" RelX="-1.0" RelY="0.0" /> <Point X="63.0" Y="362.0" GraphRef="d9c5b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783681" /> </Interaction> <Interaction GraphId="b8200"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="107.0" Y="995.0" GraphRef="fa6d1" RelX="0.4199999999999875" RelY="0.5299999999999727" /> <Point X="129.0" Y="998.0" GraphRef="f310a" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783552" /> </Interaction> <Interaction GraphId="b8aa6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="167.0" Y="1042.0" GraphRef="ef9ae" RelX="-1.9399999999999977" RelY="1.7799999999999727" /> <Point X="187.0" Y="1063.0" GraphRef="bfe5e" RelX="0.9826086956521739" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783524" /> </Interaction> <Interaction GraphId="ba5a4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1467.0" Y="268.0" GraphRef="d2712" RelX="0.650000000000091" RelY="0.0" /> <Point X="1509.0" Y="222.0" GraphRef="edcbe" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112514" /> </Interaction> <Interaction GraphId="baa49"> <Comment Source="Reactome">In untreated cells STAT1 and STAT3 are distributed diffusely in the cytoplasm and nucleus. A few minutes after Interleukin-6 treatment both are preferentially located in the nucleus. This translocation is transient; after 2 hours the distribution is comparable to that of untreated cells (Zhang et al. 1995). It is believed that STATs entry to the nucleus is mediated by importins via nuclear pore complexes (NPCs) (Reich &amp; Liu 2006).</Comment> <BiopaxRef>b3c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2046.0" Y="842.0" /> <Point X="2046.0" Y="961.0" /> <Anchor Position="0.0" Shape="None" GraphId="c4cf6" /> <Anchor Position="0.99" Shape="None" GraphId="b4835" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112587" /> </Interaction> <Interaction GraphId="bb565"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1648.0" Y="626.0" GraphRef="c5768" RelX="-1.0" RelY="0.0" /> <Point X="1613.0" Y="657.0" GraphRef="caf1b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112708" /> </Interaction> <Interaction GraphId="bd13e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="220.0" Y="463.0" GraphRef="de84d" RelX="0.984251968503937" RelY="0.0" /> <Point X="253.0" Y="459.0" GraphRef="e2b2b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783556" /> </Interaction> <Interaction GraphId="bd8ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1493.0" Y="851.0" GraphRef="a77d7" RelX="-1.0" RelY="-0.012987012987012988" /> <Point X="1433.0" Y="817.0" GraphRef="cffa7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112690" /> </Interaction> <Interaction GraphId="bda38"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="600.0" Y="112.0" GraphRef="a47f2" RelX="1.0" RelY="-0.037037037037037035" /> <Point X="606.0" Y="70.0" GraphRef="e29ad" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067676" /> </Interaction> <Interaction GraphId="be049"> <Comment Source="Reactome">Members of the interleukin-6 (IL-6) cytokines, IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM) cardiotrophin-1 (CT-1) and cardiotrophin-like cytokine (CLC) share one or both of the receptor signal transducing subunits glycoprotein (gp) 130 and LIFR in their respective receptor complexes (Taga et al. 1997). gp130 (also known as CD130) is the central signal transducer of the interleukin-6 (IL6)-related cytokines. It is expressed in almost all organs, including heart, kidney, spleen, liver, lung, placenta, and brain. Mice lacking gp130 gene results in embryonic lethality at day 12.5 (Yoshida et al. 1996). CNTFR alpha bound to CNTFR or CLCF1:CRLF1 complex recruits gp130 by binding to the cytokine-binding domain (CBD) of gp130 (Man et al. 2003).</Comment> <BiopaxRef>a1b</BiopaxRef> <BiopaxRef>efe</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="244.0" Y="644.0" /> <Point X="224.0" Y="481.0" /> <Anchor Position="0.0" Shape="None" GraphId="e9501" /> <Anchor Position="0.99" Shape="None" GraphId="c6fec" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783530" /> </Interaction> <Interaction GraphId="be839"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="607.0" Y="243.0" GraphRef="a2f1e" RelX="0.9300000000000637" RelY="-0.28999999999999204" /> <Point X="629.0" Y="239.0" GraphRef="c5692" RelX="-0.012048192771084338" RelY="0.9428571428571428" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067688" /> </Interaction> <Interaction GraphId="bea93"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="556.0" Y="218.0" GraphRef="aa10a" RelX="0.9764705882352941" RelY="-0.02702702702702703" /> <Point X="888.0" Y="125.0" GraphRef="b90ac" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449976" /> </Interaction> <Interaction GraphId="bf18f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2144.0" Y="224.0" GraphRef="e27c2" RelX="0.9574468085106383" RelY="0.0" /> <Point X="2354.0" Y="302.0" GraphRef="a999d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696490" /> </Interaction> <Interaction GraphId="bf22c"> <Comment Source="Reactome">Ciliary neurotrophic factor (CNTF) is a cytokine a member of the interleukin-6 (IL6) family, expressed in glial cells within the central and peripheral nervous systems. It stimulates gene expression, cell survival or differentiation in a variety of neuronal cell types such as sensory, sympathetic, ciliary and motor neurons. CNTF is not essential for neural development, but instead acts in response to injury or other stresses. CNTF transduces signal by binding to its receptor complex. This receptor complex consists of a ligand-binding component, CNTF receptor (CNTFR), associated with two signaling receptor components, gp130 and leukemia inhibitory factor receptor (LIFR). The three CNTF receptor components are initially unassociated on the cell surface, and are brought together in step-wise fashion upon CNTF binding. CNTF first binds to CNTFR alpha, then recruits gp130, and finally complexes with LIFR beta (Sleeman et al. 2000, Stahl &amp; Yancopoulos 1994, Robledo et al. 1996).</Comment> <BiopaxRef>a60</BiopaxRef> <BiopaxRef>a71</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2169.0" Y="192.0" /> <Point X="2212.0" Y="203.0" /> <Anchor Position="0.0" Shape="None" GraphId="ad8c1" /> <Anchor Position="0.99" Shape="None" GraphId="b0a2c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696491" /> </Interaction> <Interaction GraphId="bfabc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2488.0" Y="234.0" GraphRef="a86cb" RelX="1.3400000000001455" RelY="-0.6800000000000068" /> <Point X="2503.0" Y="231.0" GraphRef="e6843" RelX="-0.007751937984496124" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696490" /> </Interaction> <Interaction GraphId="bfb57"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="747.0" Y="201.0" GraphRef="b6c1b" RelX="0.5499999999999545" RelY="0.5799999999999841" /> <Point X="753.0" Y="204.0" GraphRef="b4cee" RelX="-0.010526315789473684" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067651" /> </Interaction> <Interaction GraphId="c0494"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="109.0" Y="699.0" GraphRef="c0fae" RelX="0.9487179487179487" RelY="0.0" /> <Point X="266.0" Y="699.0" GraphRef="c28d1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696482" /> </Interaction> <Interaction GraphId="c0c8f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="491.0" Y="240.0" GraphRef="d4ca1" RelX="0.8400000000000318" RelY="-0.3400000000000034" /> <Point X="514.0" Y="236.0" GraphRef="aa10a" RelX="-0.011764705882352941" RelY="0.9459459459459459" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067646" /> </Interaction> <Interaction GraphId="c2353"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1467.0" Y="268.0" GraphRef="d2712" RelX="0.650000000000091" RelY="0.0" /> <Point X="1495.0" Y="309.0" GraphRef="aa262" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112514" /> </Interaction> <Interaction GraphId="c3c20"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="224.0" Y="481.0" GraphRef="c6fec" RelX="-0.19999999999998863" RelY="-1.6299999999999955" /> <Point X="220.0" Y="463.0" GraphRef="de84d" RelX="0.984251968503937" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783530" /> </Interaction> <Interaction GraphId="c477e"> <Comment Source="Reactome">Leukemia inhibitory factor (LIF), initially named for its ability to cause myeloid leukemic cells to differentiate into macrophages (Gearing et al. 1987) is a member of the interleukin-6 (IL-6)-related cytokines. It possesses overlapping function with other IL-6 family members. The pleiotrophic effects of LIF in many physiological systems include proliferation, differentiation, and cell survival (Hilton 1992, Metcalf 1992). It exerts numerous effects in the nervous system, promote gliogenesis, support neural stem cell (NSC) renewal (Bonni et al. 1997, Hermanson et al. 2002, Pitman et al. 2004) and also been implicated in the expression of various cytokines. LIF exerts its effects by binding to a bipartite membrane receptor complex that consists of the LIF receptor subunit (LIFR) and the glycoprotein (gp)130 subunit and activates STAT3. LIF initially binds LIFR and the LIFR Ig-like domains contributes to LIF binding (Bitard et al. 2003).</Comment> <BiopaxRef>c37</BiopaxRef> <BiopaxRef>e66</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="63.0" Y="362.0" /> <Point X="103.0" Y="402.0" /> <Anchor Position="0.0" Shape="None" GraphId="d9c5b" /> <Anchor Position="0.99" Shape="None" GraphId="eb75a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783681" /> </Interaction> <Interaction GraphId="c52da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="600.0" Y="112.0" GraphRef="a47f2" RelX="1.0" RelY="-0.037037037037037035" /> <Point X="692.0" Y="143.0" GraphRef="e798c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067651" /> </Interaction> <Interaction GraphId="c5c60"> <Comment Source="Reactome">The tyrosine kinases JAK1, JAK2 and Tyk2 associate with the cytoplasmic domain of the interleukin-6 receptor beta subunit (IL6ST, GP130) (Stahl et al. 1994), via interactions with the membrane proximal Box1/Box2 region, motifs conserved amongst many cytokine receptors. This region of IL6ST is sufficient for JAK activation (Narazaki et al. 1994). The interbox region is also involved in JAK binding (Haan et al. 2000). This is a strong and stable assocation considered to be constitutive (Heinrich et al. 2003). The N-terminal region of JAK1 contains a FERM domain that is crucial for receptor association (Haan et al. 2001, Hilkens et al. 2001). Interleukin-6 (IL6) induces rapid phosphorylation and activation of JAK1, JAK2 and TYK2 in cells (Guschin et al. 1995), but experiments in JAK1 deficient cell lines (Guschin et al. 1995) and Jak1 -/- mice (Rodig et al. 1998) where IL6-induced responses (Il6st phosphorylation and actvation of Stat1 and Stat3) were greatly impaired, suggest that JAK1 is the key kinase for signal transduction. One possible model is that JAK1 associates with IL6ST and triggers downstream events, but requires either JAK2 or TYK2 for efficient activation or ligand-induced dimerization of the receptor complex.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="407.0" Y="274.0" /> <Point X="491.0" Y="240.0" /> <Anchor Position="0.0" Shape="None" GraphId="ab5da" /> <Anchor Position="0.99" Shape="None" GraphId="d4ca1" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067646" /> </Interaction> <Interaction GraphId="c62d6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="514.0" Y="236.0" GraphRef="aa10a" RelX="-0.011764705882352941" RelY="0.9459459459459459" /> <Point X="514.0" Y="272.0" GraphRef="ff4f6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067688" /> </Interaction> <Interaction GraphId="c6c80"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2212.0" Y="203.0" GraphRef="b0a2c" RelX="0.4299999999998363" RelY="0.11000000000001364" /> <Point X="2226.0" Y="206.0" GraphRef="ff20c" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696491" /> </Interaction> <Interaction GraphId="c6fa5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1680.0" Y="269.0" GraphRef="e02fd" RelX="0.6199999999998909" RelY="0.0" /> <Point X="1694.0" Y="304.0" GraphRef="b33bf" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112510" /> </Interaction> <Interaction GraphId="c72e2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1680.0" Y="269.0" GraphRef="e02fd" RelX="0.6199999999998909" RelY="0.0" /> <Point X="1729.0" Y="226.0" GraphRef="dec65" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112510" /> </Interaction> <Interaction GraphId="c9de0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="961.0" Y="220.0" GraphRef="a0605" RelX="-1.0" RelY="0.0" /> <Point X="959.0" Y="184.0" GraphRef="ccfed" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449829" /> </Interaction> <Interaction GraphId="ca369"> <Comment Source="Reactome">The complex of interleukin-6 (IL6) and the soluble, short form of the IL6 receptor (IL6R-2) binds to surface expressed IL6ST (gp130), a process known as trans signaling (Rose-John et al. 2006). This process is negatively regulated by the soluble form of IL6ST (IL6ST-2).</Comment> <BiopaxRef>ae7</BiopaxRef> <BiopaxRef>c48</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="692.0" Y="143.0" /> <Point X="747.0" Y="201.0" /> <Anchor Position="0.0" Shape="None" GraphId="e798c" /> <Anchor Position="0.99" Shape="None" GraphId="b6c1b" /> <Anchor Position="0.5" Shape="None" GraphId="ae0f2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067651" /> </Interaction> <Interaction GraphId="cb3a3"> <Comment Source="Reactome">Interleukin-6 (IL6) activates the tyrosine phosphorylation of STATs (Akira et al. 1994, Zhong et al. 1994) by receptor-associated JAKs (Hemmann et al. 1996) at a site that is essential for dimerization. For STAT1 this is tyrosine-701, for STAT3 tyrosine-705 (Kaptein et al. 1996, Shuai et al. 1994). Tyrosine phosphorylation leads to homo- or heterodimerization and translocation to the nucleus (Zhong et al. 1994), where the dimers bind to enhancers of IL6- inducible genes e.g. acute phase protein genes, resulting in transcriptional activation.</Comment> <BiopaxRef>e29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2545.0" Y="485.0" /> <Point X="2545.0" Y="551.0" /> <Anchor Position="0.0" Shape="None" GraphId="f9565" /> <Anchor Position="0.99" Shape="None" GraphId="f50f4" /> <Anchor Position="0.5" Shape="None" GraphId="dc1e4" /> <Anchor Position="0.5" Shape="None" GraphId="e834f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="cba82"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="305.0" Y="79.0" GraphRef="d908f" RelX="1.0" RelY="-0.034482758620689655" /> <Point X="352.0" Y="113.0" GraphRef="c1cd6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067640" /> </Interaction> <Interaction GraphId="cdfa8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2046.0" Y="961.0" GraphRef="b4835" RelX="0.0" RelY="1.1900000000000546" /> <Point X="2047.0" Y="967.0" GraphRef="af679" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112587" /> </Interaction> <Interaction GraphId="cf011"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="375.0" Y="205.0" GraphRef="c750b" RelX="0.7900000000000205" RelY="0.28999999999999204" /> <Point X="390.0" Y="208.0" GraphRef="e3210" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067667" /> </Interaction> <Interaction GraphId="cfd3b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2519.0" Y="404.0" GraphRef="c8138" RelX="5.510000000000218" RelY="0.06999999999999318" /> <Point X="2522.0" Y="405.0" GraphRef="cfebb" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112565" /> </Interaction> <Interaction GraphId="d015e"> <Comment Source="Reactome">Leukemia inhibitory factor receptor (LIFR) beta and Oncostatin M receptor (OSMR) constitutively associates with the JAK-TYK family of cytoplasmic protein tyrosine kinases in the absence of ligand. Activation of these kinases occur as a result of ligand-induced heterodimerzation of LIFR beta or OSMR with gp130 (Stahl et al. 1994, Hermanns et al. 2000).</Comment> <BiopaxRef>aad</BiopaxRef> <BiopaxRef>fca</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="398.0" Y="983.0" /> <Point X="153.0" Y="1118.0" /> <Anchor Position="0.0" Shape="None" GraphId="fbcfb" /> <Anchor Position="0.99" Shape="None" GraphId="fd733" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784204" /> </Interaction> <Interaction GraphId="d02a8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="375.0" Y="333.0" GraphRef="a5676" RelX="0.0" RelY="0.9487179487179487" /> <Point X="398.0" Y="983.0" GraphRef="fbcfb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784204" /> </Interaction> <Interaction GraphId="d093b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2069.0" Y="227.0" GraphRef="a0051" RelX="1.0" RelY="0.0" /> <Point X="2545.0" Y="522.0" GraphRef="e834f" RelX="0.0" RelY="4.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="d0c8c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="300.0" Y="233.0" GraphRef="bf007" RelX="0.0" RelY="0.9130434782608695" /> <Point X="361.0" Y="864.0" GraphRef="b323a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783524" /> </Interaction> <Interaction GraphId="d1d09"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1878.0" Y="259.0" GraphRef="c75e1" RelX="0.0" RelY="-1.0" /> <Point X="1884.0" Y="248.0" GraphRef="f9903" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112755" /> </Interaction> <Interaction GraphId="d2076"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="423.0" Y="220.0" GraphRef="e3210" RelX="1.0" RelY="0.0" /> <Point X="514.0" Y="272.0" GraphRef="ff4f6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067688" /> </Interaction> <Interaction GraphId="d20da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="246.0" Y="221.0" GraphRef="b97cc" RelX="0.9622641509433962" RelY="0.0" /> <Point X="296.0" Y="176.0" GraphRef="dbe86" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067667" /> </Interaction> <Interaction GraphId="d2ba8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2594.0" Y="641.0" GraphRef="a7ed6" RelX="0.0" RelY="1.0" /> <Point X="2561.0" Y="681.0" GraphRef="a1dcd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112727" /> </Interaction> <Interaction GraphId="d2ef6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1619.0" Y="851.0" GraphRef="a77d7" RelX="1.0" RelY="-0.012987012987012988" /> <Point X="1683.0" Y="817.0" GraphRef="bafde" RelX="-1.5" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112703" /> </Interaction> <Interaction GraphId="d340c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2493.0" Y="666.0" GraphRef="ae31d" RelX="1.0" RelY="0.0" /> <Point X="2561.0" Y="681.0" GraphRef="a1dcd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112727" /> </Interaction> <Interaction GraphId="d3dc6"> <Comment Source="Reactome">Following Interleukin-6 (IL6) stimulation, Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2) is recruited to IL6ST (gp130) phosphotyrosine-759 and is subsequently tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Mutation of Tyr-759 impairs PTPN11 recruitment and phosphorylation (Schaper et al. 1998). &lt;br&gt;There is a consensus that PTPN11 is involved in IL6-induced activation of the MAPK pathway but the molecular details are uncertain, in particular it is not clear whether the phosphatase activity of PTPN11 is required. Two pathways have been linked with activation of MAPK. One proposed mechanism is that PTPN11 acts as an adaptor for Growth factor receptor-bound protein 2-Son of sevenless homolog 1 (GRB2-SOS1) recruitment (Fukada et al. 1996, Kim &amp; Baumann 1999). Kim &amp; Baumann demonstrate IL6 induced PTPN11 recruitment to p-Tyr-759 of IL6ST but note that relatively little of the PTPN11 remains associated with IL6ST, suggesting that PTPN11 dissociates from the receptors when phosphorylated. This seems inconsistent with a GRB2:SOS1 recruitment role for PTPN11, though it is possible that only low levels or transient recruitment are required. Kim &amp; Baumann demonstrated that IL6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of PTPN11, whereas a PTPN11 mutant missing the GRB2 interaction region significantly suppressed ERK activation. This suggests that phosphatase activity is not required for ERK activation while PTPN11 interaction with GRB2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). PTPN11 and the adaptor protein GRB2-associated-binding protein 1 (GAB1) have been reported to couple IL6ST signalling to ERK activation. In this proposal phosphorylated PTPN11 dissociates from IL6ST and becomes associated with membrane associated GAB1 in a complex with PI3-kinases (Takahashi-Tezuka et al. 1998, Eulenfeld &amp; Schaper 2009). PTPN11 interaction is suggested to induce a conformational change in GAB1 that permits GAB1-PI3-kinase activation and enhancement of IL6-induced ERK pathway activation. However this is speculative, the role of PTPN11 phosphatase function is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL6 and its interaction with IL6ST.</Comment> <BiopaxRef>d5d</BiopaxRef> <BiopaxRef>b56</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1613.0" Y="657.0" /> <Point X="1567.0" Y="810.0" /> <Anchor Position="0.0" Shape="None" GraphId="caf1b" /> <Anchor Position="0.99" Shape="None" GraphId="d75c4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112708" /> </Interaction> <Interaction GraphId="d4460"> <Comment Source="Reactome">Cardiotrophin-1 (CTF1/CT-1) is a member of the IL-6 family of cytokines which was originally discovered as a factor which can induce hypertrophy of cardiac myocytes both in vitro and in vivo (Pennica et al. 1995a). Subsequently, CTF1 has been shown to have a wide variety of different effects on cardiac and non cardiac cells including the ability to stimulate the survival of both cardiac and neuronal cells (Latchman 1999). Leukemia inhibitory factor (LIF), CTF1, and oncostatin M (OSM) are four helix bundle cytokines acting through a common heterodimeric receptor composed of gp130 and LIF receptor (LIFR) (Pennica et al. 1995b).</Comment> <BiopaxRef>da4</BiopaxRef> <BiopaxRef>f3a</BiopaxRef> <BiopaxRef>a4a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="266.0" Y="699.0" /> <Point X="190.0" Y="740.0" /> <Anchor Position="0.0" Shape="None" GraphId="c28d1" /> <Anchor Position="0.99" Shape="None" GraphId="fff3d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696482" /> </Interaction> <Interaction GraphId="d5c58"> <Comment Source="Reactome">Interleukin-6 (IL6) site I interacts with Interleukin-6 receptor subunit alpha (IL6R), which is non-signaling but ligand specific.</Comment> <BiopaxRef>ae7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="296.0" Y="176.0" /> <Point X="375.0" Y="205.0" /> <Anchor Position="0.0" Shape="None" GraphId="dbe86" /> <Anchor Position="0.99" Shape="None" GraphId="c750b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067667" /> </Interaction> <Interaction GraphId="d644b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="163.0" Y="345.0" GraphRef="fe793" RelX="-0.19999999999998863" RelY="0.3299999999999841" /> <Point X="160.0" Y="354.0" GraphRef="e4534" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784189" /> </Interaction> <Interaction GraphId="d6da8"> <Comment Source="Reactome">The Interleukin-11 receptor alpha chain (IL11RA) belongs to the IL6 receptor family. Interleukin-11 (IL11) first interacts with IL11RA with a low affinity (Kd = 10 nM) forming an IL11:IL11RA complex which subsequently interacts with Interleukin-6 receptor beta subunit (IL6ST,gp130) forming a high-affinity (Kd = 300–800 pM) and signal-transducing complex (Yin et al. 1993, Hilton et al. 1994).</Comment> <BiopaxRef>d52</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="959.0" Y="184.0" /> <Point X="882.0" Y="207.0" /> <Anchor Position="0.0" Shape="None" GraphId="ccfed" /> <Anchor Position="0.99" Shape="None" GraphId="a9e96" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449829" /> </Interaction> <Interaction GraphId="d7026"> <Comment Source="Reactome">The molecular mechanism of Jak activation upon cytokine stimulation is not understood in detail (Haan et al. 2008). Cytokine-induced receptor aggregation and the resulting close proximity of Jaks bound to the beta receptor subunit is believed to trigger trans-phosphorylation of Jak tyrosines in their kinase activation loop, confering kinase activity. This active state is believed to be maintained by further autocatalytic tyrosine phosphorylations. For JAK1 the activation loop tyrosine residues are predicted by homology with models of JAK2 (Lindauer et al. 2001) to be Tyr-1034/1035. Mutation of Tyr-1034 abolishes JAK1 kinase activity (Liu et al. 1997). Evidence supporting JAK1 transphosphorylation includes JAK1 mutant cell lines, which cannot activate Tyk2 after stimulation with interferon alpha/beta (Velazquez et al. 1995) and the observation that IL-2 cannot activate JAK1 in the absence of JAK3 (Oakes et al. 1996). The receptor is not merely a docking site for JAKs as certain gp130 residues are required for JAK1 activation, but not essential for JAK1 binding (Haan et al. 2002).</Comment> <BiopaxRef>aad</BiopaxRef> <BiopaxRef>a00</BiopaxRef> <BiopaxRef>f52</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1402.0" Y="268.0" /> <Point X="1467.0" Y="268.0" /> <Anchor Position="0.0" Shape="None" GraphId="c1f48" /> <Anchor Position="0.99" Shape="None" GraphId="d2712" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112514" /> </Interaction> <Interaction GraphId="d75a5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1456.0" Y="774.0" GraphRef="af737" RelX="-1.0" RelY="0.0" /> <Point X="1433.0" Y="817.0" GraphRef="cffa7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112690" /> </Interaction> <Interaction GraphId="d76aa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="198.0" Y="647.0" GraphRef="e5ba0" RelX="1.0" RelY="0.0" /> <Point X="244.0" Y="644.0" GraphRef="e9501" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783530" /> </Interaction> <Interaction GraphId="d956e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="40.0" Y="917.0" GraphRef="fc99f" RelX="0.0" RelY="1.0" /> <Point X="65.0" Y="942.0" GraphRef="c26d9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783552" /> </Interaction> <Interaction GraphId="da717"> <Comment Source="Reactome">Glycoprotein (gp)130 is the common signal transducer for LIF, OSM and CTF1 receptor complexes. gp130/OSMRbeta complex is used solely by OSM, the gp130/LIFR complex is shared by the three receptors LIF, OSM and CTF1. Binding of OSM to either the gp130/LIFR or the gp130/OSMRbeta complex triggers the activation of multiple members of the Janus kinase (JAK) family.</Comment> <BiopaxRef>a50</BiopaxRef> <BiopaxRef>c37</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="361.0" Y="864.0" /> <Point X="167.0" Y="1042.0" /> <Anchor Position="0.0" Shape="None" GraphId="b323a" /> <Anchor Position="0.99" Shape="None" GraphId="ef9ae" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783524" /> </Interaction> <Interaction GraphId="dbfec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2545.0" Y="551.0" GraphRef="f50f4" RelX="0.0" RelY="0.6599999999999682" /> <Point X="2594.0" Y="577.0" GraphRef="a7ed6" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="dd6b6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="521.0" Y="112.0" GraphRef="bdbf4" RelX="1.6900000000000546" RelY="-0.010000000000005116" /> <Point X="524.0" Y="112.0" GraphRef="a47f2" RelX="-1.0" RelY="-0.037037037037037035" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067640" /> </Interaction> <Interaction GraphId="ddc84"> <Comment Source="Reactome">The cytokine receptor gp130 is the shared signalling subunit of the interleukin (IL)-6-type cytokines. IL-6 and IL-11 signal through gp130 homodimer whereas leukaemia inhibitory factor (LIF), ciliary neurotrophic factor receptor (CNTFR), Cardiotrophin-like cytokine factor 1 (CLCF1), Cardiotrophin-1 (CT-1) and Oncostatin-M (OSM) exerts its action through a heterodimer of gp130 and the LIF receptor (LIFR) (Heinrich et al. 2003, Giese et al. 2005). LIFR beta structure closely resembles that of gp130 and upon ligand binding forms gp130:LIFR beta heterodimer. Finally CNTFR alpha complexed with this signal transducing heterodimer converts into functional tripartite CNTF receptor and induces phosphorylation of both gp130 and LIFR beta (Davis et al. 1993, Stahl &amp; Yancopoulos 1994). Formation of the tripartite complex then leads to activation of Janus family kinases, JAK1, 2, 3, and TYK2 and phosphorylation of tyrosine residues on the cytoplasmic domain of gp130 (Kass 2011).</Comment> <BiopaxRef>cf2</BiopaxRef> <BiopaxRef>e06</BiopaxRef> <BiopaxRef>c61</BiopaxRef> <BiopaxRef>d2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="253.0" Y="459.0" /> <Point X="206.0" Y="580.0" /> <Anchor Position="0.0" Shape="None" GraphId="e2b2b" /> <Anchor Position="0.99" Shape="None" GraphId="d5ffb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783556" /> </Interaction> <Interaction GraphId="de441"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="475.0" GraphRef="b0817" RelX="-6.759999999999991" RelY="-1.330000000000041" /> <Point X="1981.0" Y="639.0" GraphRef="d41c8" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112604" /> </Interaction> <Interaction GraphId="e0c42"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="291.0" Y="134.0" GraphRef="d719d" RelX="1.0" RelY="0.0" /> <Point X="352.0" Y="113.0" GraphRef="c1cd6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067640" /> </Interaction> <Interaction GraphId="e11f8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="472.0" Y="218.0" GraphRef="aa10a" RelX="-1.0" RelY="-0.02702702702702703" /> <Point X="244.0" Y="644.0" GraphRef="e9501" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783530" /> </Interaction> <Interaction GraphId="e1df2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="375.0" Y="295.0" GraphRef="a5676" RelX="0.0" RelY="-1.0" /> <Point X="407.0" Y="274.0" GraphRef="ab5da" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067646" /> </Interaction> <Interaction GraphId="e2abf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="327.0" Y="222.0" GraphRef="bf007" RelX="1.0" RelY="-0.043478260869565216" /> <Point X="407.0" Y="274.0" GraphRef="ab5da" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067646" /> </Interaction> <Interaction GraphId="e2cf5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2047.0" Y="835.0" GraphRef="fe16d" RelX="0.0" RelY="0.9746835443037974" /> <Point X="2046.0" Y="842.0" GraphRef="c4cf6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112587" /> </Interaction> <Interaction GraphId="e2e41"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1941.0" Y="443.0" GraphRef="c5196" RelX="-0.010752688172043012" RelY="-1.0" /> <Point X="1968.0" Y="397.0" GraphRef="c1ff7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112565" /> </Interaction> <Interaction GraphId="e3c59"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="863.0" Y="210.0" GraphRef="dd824" RelX="-0.012658227848101266" RelY="-1.0" /> <Point X="888.0" Y="125.0" GraphRef="b90ac" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-449976" /> </Interaction> <Interaction GraphId="e4450"> <Comment Source="Reactome">The short, soluble form of Interleukin-6 receptor alpha (IL6R-2, sIL6R), like the longer membrane-associated form IL6R, binds circulating Interleukin-6 (IL6). IL6R-2 is generated by limited proteolysis of the longer membrane associated form and by translation of an alternatively spliced mRNA. The IL6:IL6R-2 dimer can associate with the IL6 receptor signaling beta subunit IL6ST (gp130) and stimulate cells that do not express IL6R, a process termed trans-signaling. IL6ST is expressed in many cell types that do not express IL6R (Rose-John et al. 2006).</Comment> <BiopaxRef>ae7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="352.0" Y="113.0" /> <Point X="521.0" Y="112.0" /> <Anchor Position="0.0" Shape="None" GraphId="c1cd6" /> <Anchor Position="0.99" Shape="None" GraphId="bdbf4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067640" /> </Interaction> <Interaction GraphId="e4a88"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="270.0" Y="147.0" GraphRef="d719d" RelX="0.0" RelY="1.0" /> <Point X="296.0" Y="176.0" GraphRef="dbe86" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067667" /> </Interaction> <Interaction GraphId="e50e0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2381.0" Y="205.0" GraphRef="be71b" RelX="0.32999999999992724" RelY="0.1599999999999966" /> <Point X="2385.0" Y="208.0" GraphRef="d4019" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783670" /> </Interaction> <Interaction GraphId="e53b8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1791.0" Y="258.0" GraphRef="dec65" RelX="0.0" RelY="1.0" /> <Point X="1613.0" Y="657.0" GraphRef="caf1b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112708" /> </Interaction> <Interaction GraphId="e5e9f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2561.0" Y="739.0" GraphRef="d564d" RelX="0.0" RelY="0.5800000000000409" /> <Point X="2483.0" Y="804.0" GraphRef="f5527" RelX="0.9512195121951219" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112727" /> </Interaction> <Interaction GraphId="e7384"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2044.0" Y="751.0" GraphRef="cad26" RelX="0.009999999999990905" RelY="0.8099999999999454" /> <Point X="2047.0" Y="757.0" GraphRef="fe16d" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112538" /> </Interaction> <Interaction GraphId="e771d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2499.0" Y="609.0" GraphRef="a7ed6" RelX="-1.0" RelY="0.0" /> <Point X="2496.0" Y="608.0" GraphRef="d2d46" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112604" /> </Interaction> <Interaction GraphId="e7907"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2144.0" Y="224.0" GraphRef="e27c2" RelX="0.9574468085106383" RelY="0.0" /> <Point X="2169.0" Y="192.0" GraphRef="ad8c1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696491" /> </Interaction> <Interaction GraphId="e79ea"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1942.0" Y="240.0" GraphRef="b662b" RelX="0.5799999999999272" RelY="-0.0800000000000125" /> <Point X="1945.0" Y="227.0" GraphRef="a0051" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112755" /> </Interaction> <Interaction GraphId="e803b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1622.0" Y="791.0" GraphRef="cb49c" RelX="0.0" RelY="1.0" /> <Point X="1657.0" Y="817.0" GraphRef="a98b3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112703" /> </Interaction> <Interaction GraphId="e8499"> <Comment Source="Reactome">PTPN11 (SHP2) is tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Cells lacking JAK1 showed drastically reduced PTPN11 phosphorylation following Interleuikin-6 (IL6) treatment, but it is not entirely clear whether JAK1 directly phosphorylates PTPN11 or alternatively is required for IL6ST activation, which indirectly leads to PTPN11 phosphorylation (Schaper et al, 1998). PTPN11 tyrosine phosphorylation at Y546 or Y584 (usually described as Y542 or Y580 in literature references where numbering is based on a short isoform) relieves the PTP domain from the N-SH2 domain-mediated inhibition (Lu et al. 2001). Studies using catalytically-inactive PTPN11 (Symes et al. 1997) suggest that it may dephosphorylate IL6ST and/or associated signaling factors such as JAKs and STATs, limiting acute phase gene expression (Kim and Baumann, 1999). There is a consensus that SHP2 is involved in IL6-induced activation of the MAPK pathway, but the molecular details are unclear.</Comment> <BiopaxRef>e05</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1657.0" Y="817.0" /> <Point X="1712.0" Y="817.0" /> <Anchor Position="0.0" Shape="None" GraphId="a98b3" /> <Anchor Position="0.99" Shape="None" GraphId="c1e18" /> <Anchor Position="0.5" Shape="None" GraphId="bafde" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112703" /> </Interaction> <Interaction GraphId="e8aed"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1853.0" Y="226.0" GraphRef="dec65" RelX="1.0" RelY="0.0" /> <Point X="1968.0" Y="397.0" GraphRef="c1ff7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112565" /> </Interaction> <Interaction GraphId="e9af5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2385.0" Y="230.0" GraphRef="d4019" RelX="0.0" RelY="1.0" /> <Point X="2354.0" Y="302.0" GraphRef="a999d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696490" /> </Interaction> <Interaction GraphId="ea1cb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="147.0" Y="245.0" GraphRef="d3ae8" RelX="1.0" RelY="0.0" /> <Point X="183.0" Y="312.0" GraphRef="b8602" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6784189" /> </Interaction> <Interaction GraphId="ec5da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="90.0" Y="901.0" GraphRef="c37d9" RelX="-1.0" RelY="0.0" /> <Point X="65.0" Y="942.0" GraphRef="c26d9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783552" /> </Interaction> <Interaction GraphId="ed49d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1340.0" Y="818.0" GraphRef="aac08" RelX="-0.9300000000000637" RelY="0.009999999999990905" /> <Point X="1336.0" Y="822.0" GraphRef="abad6" RelX="0.9888268156424581" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112690" /> </Interaction> <Interaction GraphId="edbef"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1383.0" Y="312.0" GraphRef="fd836" RelX="1.0" RelY="0.0" /> <Point X="1402.0" Y="268.0" GraphRef="c1f48" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112514" /> </Interaction> <Interaction GraphId="ef4f9"> <Comment Source="Reactome">Activated JAKs are believed to be responsible for phosphorylating the cytoplasmic region of IL6ST (gp130) (Wang &amp; Fuller 1994, Reich &amp; Liu 2006) creating docking sites for adaptor and downstream signaling molecules, in particular the factors STAT1 and STAT3. Several phosphotyrosine residues of IL6ST are docking sites for STATs (Stahl et al. 1995, Gerhartz et al. 1996), Tyr-759 phosphorylation allows recruitment of the phosphatase SHP2.</Comment> <BiopaxRef>b8d</BiopaxRef> <BiopaxRef>da1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1618.0" Y="269.0" /> <Point X="1680.0" Y="269.0" /> <Anchor Position="0.0" Shape="None" GraphId="ea160" /> <Anchor Position="0.99" Shape="None" GraphId="e02fd" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112510" /> </Interaction> <Interaction GraphId="efb1c"> <Comment Source="Reactome">The complex of interleukin-6 (IL6) bound to the IL6 receptor alpha subunit (IL6R) binds the IL-6 receptor beta subunit IL6ST (gp130), which constitutively binds JAK kinases. Site II of IL6 interacts with the cytokine binding-homology region of IL6ST. Subsequently, site III of IL6 interacts with the IL6ST immunoglobulin-like activation domain.</Comment> <BiopaxRef>ae7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="514.0" Y="272.0" /> <Point X="607.0" Y="243.0" /> <Anchor Position="0.0" Shape="None" GraphId="ff4f6" /> <Anchor Position="0.99" Shape="None" GraphId="a2f1e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1067688" /> </Interaction> <Interaction GraphId="efd52"> <Comment Source="Reactome">Leukemia inhibitory factor receptor (LIFR) beta and Oncostatin M receptor (OSMR) constitutively associates with the JAK-TYK family of cytoplasmic protein tyrosine kinases in the absence of ligand. 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This stimulation-dependent ubiquitination was mediated by CBL, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. The vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. 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It belongs to the interleukin-6 (IL-6) subfamily and shares properties with all the members of the family but is closely related to leukemia inhibitory factor (LIF) structurally and functionally and it infact utilizes the LIF receptor (LIFR) in addition to its specific receptor OSMR. In humans, there are two types of functional OSM receptor complexes: the type I OSM receptor complex consisting of gp130 and LIF receptor (LIFR) subunits, and the type II OSM receptor complex consisting of gp130 and OSM receptor beta (OSMRbeta) subunits (Chen &amp; Benveniste 2004, Thoma et al. 1994, Gomez-Lechon 1999). Upon association with its specific receptor complexes OSM, then activates two major signaling pathways: Janus Kinase-Signal Transducers and Activators of Transcription (JAK-STAT) and Mitogen-Activated Protein Kinase (MAPK), to regulate downstream events. OSM is involved in the regulation of complex cellular processes such as growth regulation, differentiation, gene expression, and cell survival in humans (Tanaka &amp; Miyajima 2004).</Comment> <BiopaxRef>a50</BiopaxRef> <BiopaxRef>fb9</BiopaxRef> <BiopaxRef>b1a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="65.0" Y="942.0" /> <Point X="107.0" Y="995.0" /> <Anchor Position="0.0" Shape="None" GraphId="c26d9" /> <Anchor Position="0.99" Shape="None" GraphId="fa6d1" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783552" /> </Interaction> <Interaction GraphId="f89cc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2495.0" Y="461.0" GraphRef="ed895" RelX="1.0" RelY="0.0" /> <Point X="2545.0" Y="485.0" GraphRef="f9565" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="f8a55"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="206.0" Y="580.0" GraphRef="d5ffb" RelX="-0.46999999999999886" RelY="1.2100000000000364" /> <Point X="203.0" Y="580.0" GraphRef="d9bc2" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6783556" /> </Interaction> <Interaction GraphId="f8f8f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1593.0" Y="290.0" GraphRef="ea70e" RelX="0.0" RelY="-1.0" /> <Point X="1618.0" Y="269.0" GraphRef="ea160" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112510" /> </Interaction> <Interaction GraphId="f95a0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="269.0" Y="1244.0" GraphRef="b3804" RelX="1.0" RelY="0.0" /> <Point X="423.0" Y="1370.0" GraphRef="ddbc0" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-448660" /> </Interaction> <Interaction GraphId="fbdf2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2584.0" Y="444.0" GraphRef="cfebb" RelX="0.0" RelY="1.0" /> <Point X="2545.0" Y="485.0" GraphRef="f9565" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1112602" /> </Interaction> <Interaction GraphId="fc233"> <Comment Source="Reactome">On target cells ciliary neurotrophic factor (CNTF), and cardiotrophin-like cytokine factor 1 (CLCF1) first bind their specific ligand binding component, CNTF alpha-receptor (CNTFR) subunit and induce STAT3 phosphorylation (Elson et al. 2000, Lelievre et al. 2001). CNTFR then recruits glycoprotein (gp)130, and finally complexes with leukemia inhibitory factor receptor (LIFR) beta (Stahl &amp; Yancopoulos 1994).</Comment> <BiopaxRef>ffb</BiopaxRef> <BiopaxRef>e9b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2354.0" Y="302.0" /> <Point X="2488.0" Y="234.0" /> <Anchor Position="0.0" Shape="None" GraphId="a999d" /> <Anchor Position="0.99" Shape="None" GraphId="a86cb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5696490" /> </Interaction> <Interaction GraphId="fc4ed"> <Comment Source="Reactome">Interleukin-31 (IL31) signals via a heterodimeric receptor composed of Interleukin-31 receptor A (IL31RA) and the Oncostatin M receptor (OSMR). IL31 binds first to IL31RA (LeSaux et al. 2010). This initial binding is essential for subsequent binding to OSMR, possibly because binding induces a conformational change in IL31. The resulting IL31:IL31RA complex recruits OSMR, which increases the strength of IL31 binding and is essential for subsequent STAT signaling (Diveu et al. 2004, Maier et al. 2015). 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cardiotrophin-1 stimulation of cardiac fibroblast growth: roles for glycoprotein 130/leukemia inhibitory factor receptor and the endothelin type A receptor.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tsuruda T, Jougasaki M, Boerrigter G, Huntley BK, Chen HH, D'Assoro AB, Lee SC, Larsen AM, Cataliotti A, Burnett JC.</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="da1"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">16868551</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">Tracking STAT nuclear traffic.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reich NC, Liu L.</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="fb9"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8119965</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">Oncostatin M and leukemia inhibitory factor trigger overlapping and different signals through partially shared receptor complexes.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Thoma B, Bird TA, Friend DJ, Gearing DP, Dower SK.</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="e9b"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21715184</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE 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xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="e66"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">12601009</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">Mutations in the immunoglobulin-like domain of gp190, the leukemia inhibitory factor (LIF) receptor, increase or decrease its affinity for LIF.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bitard J, Daburon S, Duplomb L, Blanchard F, Vuisio P, Jacques Y, Godard A, Heath JK, Moreau JF, Taupin JL.</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="f52"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8134389</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">Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, Ihle JN, Kishimoto T, Taga T.</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="a71"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10812968</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The ciliary neurotrophic factor and its receptor, CNTFR alpha.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD, Wiegand SJ.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref 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Minvielle S, Jacques Y.</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="c48"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2261637</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">Molecular cloning and expression of an IL-6 signal transducer, gp130.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T.</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="f1f"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10777583</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">SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F.</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="d5d"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7871433</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">Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE, Yancopoulos GD.</bp:AUTHORS> 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through the gp130/Jak/STAT pathway.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L.</bp:AUTHORS> </bp:PublicationXref> </Biopax> </Pathway>

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