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    <rdfs:comment rdf:datatype="http://www.w3.org/2001/XMLSchema#string">BioPAX pathway converted from "Interleukin-6 family signaling" in the Reactome database.</rdfs:comment>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 family signaling</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 family signaling</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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-down” 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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-06-16</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-06-16</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 signaling</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 signaling</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep.  It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M. &lt;br&gt;&lt;br&gt;The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. 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 IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities&lt;br&gt;&lt;br&gt;IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref73" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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  <bp:biochemicalReaction rdf:ID="biochemicalReaction1">
    <bp:LEFT rdf:resource="#sequenceParticipant1" />
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1,JAK2,(TYK2) bind IL6ST</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1,JAK2,(TYK2) bind IL6ST</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs associate with IL6ST (gp130)</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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  <bp:protein rdf:ID="protein1">
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P40189 IL6ST</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6ST</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6ST</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:2261637, PubMed:19915009, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity).SUBUNIT Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6 (PubMed:12829785, PubMed:2261637). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM (PubMed:8999038). Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF (PubMed:8999038). Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin (PubMed:19386761). Interacts with HCK (PubMed:9406996). Interacts with INPP5D/SHIP1 (By similarity). Interacts with SRC and YES (PubMed:25731159).SUBUNIT (Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6.TISSUE SPECIFICITY Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637).INDUCTION LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.PTM Phosphorylation of Ser-782 down-regulates cell surface expression.PTM Heavily N-glycosylated (PubMed:11098061, PubMed:16335952, PubMed:19159218, PubMed:19139490, PubMed:11251120). Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding (PubMed:19915009).BIOTECHNOLOGY Two extracellular parts of IL6ST/gp130 linked to the Fc-portions of a human IgG1 antibody (sgp130Fc) inhibit IL6 trans-signaling by the IL6:IL6R complex and has no affinity of IL6 or IL6R alone (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168, PubMed:26876177).SIMILARITY Belongs to the type I cytokine receptor family. Type 2 subfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6ST:JAK1, JAK2, (TYK2) [plasma membrane]</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway (Probable). The interaction with the membrane-bound IL6R and IL6ST stimulates 'classic signaling', whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).FUNCTION IL6 is a potent inducer of the acute phase response. Rapid production of IL6 contributes to host defense during infection and tissue injury, but excessive IL6 synthesis is involved in disease pathology. In the innate immune response, is synthesized by myeloid cells, such as macrophages and dendritic cells, upon recognition of pathogens through toll-like receptors (TLRs) at the site of infection or tissue injury (Probable). In the adaptive immune response, is required for the differentiation of B cells into immunoglobulin-secreting cells. Plays a major role in the differentiation of CD4(+) T cell subsets. Essential factor for the development of T follicular helper (Tfh) cells that are required for the induction of germinal-center formation. Required to drive naive CD4(+) T cells to the Th17 lineage. Also required for proliferation of myeloma cells and the survival of plasmablast cells (By similarity).FUNCTION Acts as an essential factor in bone homeostasis and on vessels directly or indirectly by induction of VEGF, resulting in increased angiogenesis activity and vascular permeability (PubMed:17075861, PubMed:12794819). Induces, through 'trans-signaling' and synergistically with IL1B and TNF, the production of VEGF (PubMed:12794819). Involved in metabolic controls, is discharged into the bloodstream after muscle contraction increasing lipolysis and improving insulin resistance (PubMed:20823453). 'Trans-signaling' in central nervous system also regulates energy and glucose homeostasis (By similarity). Mediates, through GLP-1, crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand (By similarity). Also acts as a myokine (Probable). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). Also has a pivotal role in iron metabolism by regulating HAMP/hepcidin expression upon inflammation or bacterial infection (PubMed:15124018). Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation-induced epithelial regeneration (By similarity).SUBUNIT Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6R to associate with the signaling subunit IL6ST (PubMed:12829785). Interacts with IL6R (via the N-terminal ectodomain); this interaction may be affected by IL6R-binding with SORL1, hence decreasing IL6 cis signaling (PubMed:28265003). Interacts with SORL1 (via the N-terminal ectodomain); this interaction leads to IL6 internalization and lysosomal degradation (PubMed:28265003). May form a trimeric complex with the soluble SORL1 ectodomain and soluble IL6R receptor; this interaction might stabilize circulating IL6, hence promoting IL6 trans signaling (PubMed:28265003).TISSUE SPECIFICITY Produced by skeletal muscle.INDUCTION Plasma levels are highly increased upon exercise, due to enhanced production by contracting skeletal muscles.PTM N- and O-glycosylated.POLYMORPHISM Genetic variations in IL6 may be correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.DISEASE A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men.SIMILARITY Belongs to the IL-6 superfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P08887-2 IL6R</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).ACTIVITY REGULATION Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling.SUBUNIT Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003).DOMAIN The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.PTM A short soluble form is released from the membrane by proteolysis (PubMed:26876177). The sIL6R is formed mostly by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, but is also directly secreted from the cells after alternative mRNA splicing (PubMed:26876177, PubMed:28060820). mIL6R is cleaved by the proteases ADAM10 and ADAM17 (PubMed:26876177, PubMed:28060820).PTM Glycosylated. Glycosylation is dispensable for transport, signaling, and cell-surface turnover. Glycosylation at Asn-55 is a protease-regulatory exosite. Glycosylation is required for ADAM17-mediated proteolysis.POLYMORPHISM Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].POLYMORPHISM Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily.</bp:COMMENT>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hibi, M</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yamasaki, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yasukawa, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Matsuda, T</bp:AUTHORS>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cell 58:573-81</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer</bp:TITLE>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Leukoc Biol 80:227-36</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6R-2 binds IL6ST-2</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6R-2 binds IL6ST-2</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Soluble IL6ST (sgp130) binds to circulating Interleukin-6 (IL6) bound to the soluble form of IL6 receptor alpha (IL6:IL6R-2), preventing binding to IL6ST (gp130) on the plasma membrane, thereby specifically inhibiting IL6 trans-signaling (Jostock et al. 2001).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:2261637, PubMed:19915009, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity).SUBUNIT Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6 (PubMed:12829785, PubMed:2261637). Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM (PubMed:8999038). Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF (PubMed:8999038). Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin (PubMed:19386761). Interacts with HCK (PubMed:9406996). Interacts with INPP5D/SHIP1 (By similarity). Interacts with SRC and YES (PubMed:25731159).SUBUNIT (Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6.TISSUE SPECIFICITY Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637).INDUCTION LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.PTM Phosphorylation of Ser-782 down-regulates cell surface expression.PTM Heavily N-glycosylated (PubMed:11098061, PubMed:16335952, PubMed:19159218, PubMed:19139490, PubMed:11251120). Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding (PubMed:19915009).BIOTECHNOLOGY Two extracellular parts of IL6ST/gp130 linked to the Fc-portions of a human IgG1 antibody (sgp130Fc) inhibit IL6 trans-signaling by the IL6:IL6R complex and has no affinity of IL6 or IL6R alone (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168, PubMed:26876177).SIMILARITY Belongs to the type I cytokine receptor family. Type 2 subfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6R-2:IL6ST-2 [extracellular region]</bp:NAME>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jostock, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Müllberg, J</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blinn, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Voltz, N</bp:AUTHORS>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Eur J Biochem 268:160-7</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 binds IL6R</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 binds IL6R</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 binds to IL-6 receptor alpha subunit</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 (IL6) site I interacts with Interleukin-6 receptor subunit alpha (IL6R), which is non-signaling but ligand specific.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P08887 IL6R</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).ACTIVITY REGULATION Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling.SUBUNIT Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003).DOMAIN The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.PTM A short soluble form is released from the membrane by proteolysis (PubMed:26876177). The sIL6R is formed mostly by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, but is also directly secreted from the cells after alternative mRNA splicing (PubMed:26876177, PubMed:28060820). mIL6R is cleaved by the proteases ADAM10 and ADAM17 (PubMed:26876177, PubMed:28060820).PTM Glycosylated. Glycosylation is dispensable for transport, signaling, and cell-surface turnover. Glycosylation at Asn-55 is a protease-regulatory exosite. Glycosylation is required for ADAM17-mediated proteolysis.POLYMORPHISM Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].POLYMORPHISM Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6R [plasma membrane]</bp:NAME>
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  <bp:sequenceInterval rdf:ID="sequenceInterval12">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite23" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite24" />
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  <bp:sequenceSite rdf:ID="sequenceSite23">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">20</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
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  <bp:sequenceSite rdf:ID="sequenceSite24">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">468</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1067638</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1067638</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref25">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1067638</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1067638.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref26">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1067667</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1067667.4</bp:COMMENT>
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    <bp:CONTROL-TYPE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">INHIBITION</bp:CONTROL-TYPE>
    <bp:XREF rdf:resource="#unificationXref28" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:CONTROLLER rdf:resource="#physicalEntityParticipant7" />
    <bp:CONTROLLED rdf:resource="#biochemicalReaction4" />
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    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9690521</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=9690521</bp:COMMENT>
  </bp:unificationXref>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant7">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex5" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 9681293</bp:COMMENT>
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    <bp:COMPONENTS rdf:resource="#sequenceParticipant15" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R:IL6R inhibitors [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R:IL6R inhibitors</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref32" />
    <bp:XREF rdf:resource="#unificationXref33" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant8">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary4" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 9715042</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntity rdf:ID="physicalEntity1">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R inhibitors [extracellular region]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
    <bp:XREF rdf:resource="#unificationXref29" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">satralizumab [extracellular region]</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref30" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">tocilizumab [extracellular region]</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref31" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">sarilumab [extracellular region]</bp:SYNONYMS>
  </bp:physicalEntity>
  <bp:unificationXref rdf:ID="unificationXref29">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guide to Pharmacology</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9093</bp:ID>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref30">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guide to Pharmacology</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6881</bp:ID>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref31">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guide to Pharmacology</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7999</bp:ID>
  </bp:unificationXref>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant15">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein6" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature13" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 197824</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:sequenceFeature rdf:ID="sequenceFeature13">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval13" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval13">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite25" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite26" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite25">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">20</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite26">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">468</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:unificationXref rdf:ID="unificationXref32">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9681293</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=9681293</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref33">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-9681293</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9681293.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:pathwayStep rdf:ID="pathwayStep8">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction4" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep14" />
    <bp:STEP-INTERACTIONS rdf:resource="#control1" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction5">
    <bp:LEFT rdf:resource="#physicalEntityParticipant9" />
    <bp:LEFT rdf:resource="#sequenceParticipant16" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant10" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R binds IL6R inhibitors</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6R binds IL6R inhibitors</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref34" />
    <bp:XREF rdf:resource="#unificationXref35" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine. Its deregulation is associated with chronic inflammation, and multifactorial auto-immune disorders (Kaur et al. 2020). Tocilizumab is an anti-IL-6 receptor monoclonal antibody (mAb) with immunosuppressive action for chronic autoimmune indications such as rheumatoid arthritis (Choy et al. 2002). Satralizumab is a humanized monoclonal antibody that is approved (Heo 2020) for the treatment of neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease (Rosso et al. 2020, Duchow &amp; Bellmann-Strobl 2021). Sarilumab is a human monoclonal antibody against the interleukin-6 receptor (Xu et al. 2020) developed for the treatment of rheumatoid arthritis (Strand et al. 2020).&lt;br&gt;&lt;br&gt;In a small, uncontrolled study, Xu et al. suggest tocilizumab might attenuate the "cytokine storm" seen in Covid-19 patients by resolving high levels of IL6 and other proinflammatory cytokines (Xu et al. 2020). Sarhan et al. concluded from a small study of 25 Covid-19 patients that tocilizumab administration resulted in significant therapeutic effect and improvement of all laboratory parameters (Sarhan et al. 2021). In the much larger Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, tocilizumab administered by intravenous infusion to Covid-19 patients resulted in reduced risk of death and shortened hospitalisation times (Hornby et al. 2021 preprint https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1)). China's National Health Commission has authorised tocilizumab's use to treat patients with serious COVID-19-induced lung damage (Luo et al. 2020, Zhang et al. 2020a,b). Other IL6 inhibitors need further study to assess their efficacy in Covid-19 patients (Khan et al. 2021).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref12" />
    <bp:XREF rdf:resource="#publicationXref13" />
    <bp:XREF rdf:resource="#publicationXref14" />
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    <bp:XREF rdf:resource="#publicationXref16" />
    <bp:XREF rdf:resource="#publicationXref17" />
    <bp:XREF rdf:resource="#publicationXref18" />
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    <bp:XREF rdf:resource="#publicationXref20" />
    <bp:XREF rdf:resource="#publicationXref21" />
    <bp:XREF rdf:resource="#publicationXref22" />
    <bp:XREF rdf:resource="#publicationXref23" />
    <bp:XREF rdf:resource="#publicationXref24" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Jassal, Bijay, 2020-04-01</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Shoichet, Brian, 2020-05-14</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jassal, Bijay, 2020-04-01</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant9">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary4" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 9715042</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant16">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein6" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature14" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 197824</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:sequenceFeature rdf:ID="sequenceFeature14">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval14" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval14">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite27" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite28" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite27">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">20</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite28">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">468</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant10">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex5" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 9681293</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:unificationXref rdf:ID="unificationXref34">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9681294</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=9681294</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref35">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-9681294</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">3</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9681294.3</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref12">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">32253759</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2020</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tocilizumab treatment in COVID-19: A single center experience</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Luo, Pan</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, Yi</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Qiu, Lin</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, Xiulan</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, Dong</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li, Juan</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Med. Virol.</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref13">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">32797372</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2020</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Satralizumab: First Approval</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heo, Young-A</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Drugs 80:1477-1482</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref14">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">32306778</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2020</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Targeting IL-6 receptor in the treatment of neuromyelitis optica spectrum: a review of emerging treatment options</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rosso, Mattia</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Saxena, Shrishti</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chitnis, Tanuja</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Expert Rev Neurother 20:509-516</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref15">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">32350134</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2020</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Effective treatment of severe COVID-19 patients with tocilizumab</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Xu, X</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Han, Mingfeng</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li, Tiantian</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sun, W</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang, Dongsheng</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Fu, Binqing</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhou, Yonggang</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zheng, Xiaohu</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yang, Yun</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li, Xiuyong</bp:AUTHORS>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Molecular cloning and expression of an IL-6 signal transducer, gp130</bp:TITLE>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Murakami, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Saito, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hirano, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cell 63:1149-57</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6R binds IL6ST:JAK1,JAK2,(TYK2)</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6RA:IL6RB:JAKs [plasma membrane]</bp:NAME>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Assembly of hexameric IL-6 receptor</bp:NAME>
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    <bp:XREF rdf:resource="#unificationXref48" />
    <bp:XREF rdf:resource="#unificationXref49" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 receptor trimer:JAKs [plasma membrane]</bp:NAME>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 receptor hexamer:JAKs [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 receptor hexamer:JAKs</bp:SHORT-NAME>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2005</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Skiniotis, Georgios</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Boulanger, Martin J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Garcia, K Christopher</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Walz, Thomas</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nat. Struct. Mol. Biol. 12:545-51</bp:SOURCE>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1999</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL-6 type cytokine receptor complexes: hexamer, tetramer or both?</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Grötzinger, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kernebeck, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kallen, K J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rose-John, Stefan</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Biol. Chem. 380:803-13</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2006</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 and its receptor: from bench to bedside</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Scheller, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rose-John, Stefan</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Med Microbiol Immunol 195:173-83</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref29">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">12829785</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2003</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Boulanger, MJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chow, DC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Brevnova, EE</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Garcia, KC</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 300:2101-4</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Suthaus, Jan</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tillmann, Anna</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lorenzen, Inken</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bulanova, Elena</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rose-John, Stefan</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Scheller, Jürgen</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol. Biol. Cell 21:2797-807</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK activation</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK activation</bp:SHORT-NAME>
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    <bp:XREF rdf:resource="#unificationXref55" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">ADP(3-) [ChEBI:456216]</bp:NAME>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 receptor hexamer:Activated JAKs [plasma membrane]</bp:NAME>
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  <bp:physicalEntity rdf:ID="physicalEntity3">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6 receptor trimer:Activated JAKs [plasma membrane]</bp:NAME>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1995</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-alpha/beta and for signal transduction</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Velazquez, L</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mogensen, KE</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Barbieri, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Fellous, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Uzé, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pellegrini, S</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Biol Chem 270:3327-34</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref32">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11287676</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2001</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lindauer, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Loerting, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liedl, KR</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kroemer, RT</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Protein Eng 14:27-37</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref33">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11742534</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2002</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Structural requirements of the interleukin-6 signal transducer gp130 for its interaction with Janus kinase 1: the receptor is crucial for kinase activation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Haan, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Behrmann, I</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Biochem J 361:105-11</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref34">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18178840</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2008</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dual role of the Jak1 FERM and kinase domains in cytokine receptor binding and in stimulation-dependent Jak activation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Haan, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Margue, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Engrand, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rolvering, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schmitz-Van de Leur, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Behrmann, I</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Haan, C</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Immunol 180:998-1007</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref35">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8986719</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Signaling via IL-2 and IL-4 in JAK3-deficient severe combined immunodeficiency lymphocytes: JAK3-dependent and independent pathways</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oakes, SA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Candotti, F</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Johnston, JA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chen, YQ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ryan, JJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taylor, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, X</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hennighausen, L</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Notarangelo, LD</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Paul, WE</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blaese, RM</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">O'Shea, JJ</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Immunity 5:605-15</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref36">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9382798</bp:ID>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1997</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, KD</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gaffen, SL</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Goldsmith, MA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Greene, WC</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Curr Biol 7:817-26</bp:SOURCE>
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  <bp:pathwayStep rdf:ID="pathwayStep18">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction9" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep20" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction10">
    <bp:LEFT rdf:resource="#physicalEntityParticipant30" />
    <bp:LEFT rdf:resource="#physicalEntityParticipant31" />
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    <bp:RIGHT rdf:resource="#physicalEntityParticipant33" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6ST is tyrosine phosphorylated</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6ST is tyrosine phosphorylated</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylation of gp130</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref58" />
    <bp:XREF rdf:resource="#unificationXref59" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref37" />
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    <bp:XREF rdf:resource="#publicationXref39" />
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    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant30">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant31">
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    <bp:PHYSICAL-ENTITY rdf:resource="#complex9" />
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant32">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#smallMolecule2" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 29370</bp:COMMENT>
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant33">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112594</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex10">
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant34" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref56" />
    <bp:XREF rdf:resource="#unificationXref57" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant34">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity4" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112584</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">2</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntity rdf:ID="physicalEntity4">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6:IL6RA:Tyrosine phosphorylated IL6RB:Activated JAKs [plasma membrane]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:unificationXref rdf:ID="unificationXref56">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112594</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112594</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref57">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112594</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112594.1</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref58">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112510</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112510</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref59">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112510</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">4</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112510.4</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref37">
    <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:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2006</bp:YEAR>
    <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</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Liu, L</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nat Rev Immunol 6:602-12</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref38">
    <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:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1995</bp:YEAR>
    <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</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Farruggella, TJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Boulton, TG</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhong, Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yancopoulos, GD</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 267:1349-53</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref39">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7812050</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylation and internalization of gp130 occur after IL-6 activation of Jak2 kinase in hepatocytes</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Fuller, GM</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol Biol Cell 5:819-28</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref40">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8662591</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gerhartz, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heesel, B</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sasse, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hemmann, U</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Landgraf, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schneider-Mergener, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Horn, F</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Graeve, L</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Biol Chem 271:12991-8</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep20">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction10" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep38" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep22" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep34" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction11">
    <bp:LEFT rdf:resource="#physicalEntityParticipant35" />
    <bp:LEFT rdf:resource="#sequenceParticipant17" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant36" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6ST binds STAT1,STAT3</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6ST binds STAT1,STAT3</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STATs bind gp130 phosphotyrosines</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref64" />
    <bp:XREF rdf:resource="#unificationXref65" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref41" />
    <bp:XREF rdf:resource="#publicationXref40" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant35">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
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    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant17">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein7" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112559</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein7">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT1, STAT3 [cytosol]</bp:NAME>
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
    <bp:XREF rdf:resource="#unificationXref60" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT1 [cytosol]</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref61" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT3 [cytosol]</bp:SYNONYMS>
  </bp:protein>
  <bp:unificationXref rdf:ID="unificationXref60">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">P42224</bp:ID>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref61">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">P40763</bp:ID>
  </bp:unificationXref>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant36">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex11" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112576</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex11">
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant37" />
    <bp:COMPONENTS rdf:resource="#sequenceParticipant18" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:STAT1,STAT3 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:STAT1,STAT3</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref62" />
    <bp:XREF rdf:resource="#unificationXref63" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant37">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112594</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant18">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein7" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112559</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:unificationXref rdf:ID="unificationXref62">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112576</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112576</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref63">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112576</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112576.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref64">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112565</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112565</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref65">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112565</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">4</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112565.4</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref41">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8662795</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. II. Src homology SH2 domains define the specificity of stat factor activation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hemmann, U</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gerhartz, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heesel, B</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sasse, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kurapkat, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Grötzinger, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wollmer, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhong, Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Graeve, L</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Horn, F</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Biol Chem 271:12999-3007</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep22">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction11" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep24" />
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  <bp:biochemicalReaction rdf:ID="biochemicalReaction12">
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    <bp:LEFT rdf:resource="#physicalEntityParticipant39" />
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    <bp:EC-NUMBER rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2.7.10.2</bp:EC-NUMBER>
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylation of STAT1, STAT3 by IL6 receptor</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylation of STAT1, STAT3 by IL6 receptor</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref69" />
    <bp:XREF rdf:resource="#unificationXref70" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
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    <bp:XREF rdf:resource="#publicationXref43" />
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    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant39">
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    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine phosphorylated STAT1,STAT3 [plasma membrane]</bp:NAME>
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  <bp:sequenceParticipant rdf:ID="sequenceParticipant19">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein8" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112571</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
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  <bp:protein rdf:ID="protein8">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">p-Y701-STAT1, p-Y705-STAT3 [cytosol]</bp:NAME>
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
    <bp:XREF rdf:resource="#unificationXref61" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">p-Y705-STAT3 [cytosol]</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref60" />
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">p-Y701-STAT1 [cytosol]</bp:SYNONYMS>
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  <bp:unificationXref rdf:ID="unificationXref66">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112524</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112524</bp:COMMENT>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112524</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112524.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:catalysis rdf:ID="catalysis1">
    <bp:CONTROLLER rdf:resource="#physicalEntityParticipant43" />
    <bp:CONTROLLED rdf:resource="#biochemicalReaction12" />
    <bp:DIRECTION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PHYSIOL-LEFT-TO-RIGHT</bp:DIRECTION>
    <bp:CONTROL-TYPE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">ACTIVATION</bp:CONTROL-TYPE>
    <bp:XREF rdf:resource="#relationshipXref1" />
    <bp:XREF rdf:resource="#unificationXref68" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:catalysis>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant43">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex11" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112576</bp:COMMENT>
  </bp:physicalEntityParticipant>
  <bp:relationshipXref rdf:ID="relationshipXref1">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">GO</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">0004715</bp:ID>
    <bp:RELATIONSHIP-TYPE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">GO molecular function</bp:RELATIONSHIP-TYPE>
  </bp:relationshipXref>
  <bp:unificationXref rdf:ID="unificationXref68">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112516</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112516</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref69">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112602</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112602</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref70">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112602</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112602.6</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref42">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8626374</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kaptein, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Paillard, V</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Saunders, M</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Biol Chem 271:5961-4</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref43">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7510216</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Shuai, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Horvath, CM</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Huang, LH</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Qureshi, SA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cowburn, D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cell 76:821-8</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref44">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7512451</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Akira, Shizuo</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nishio, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Inoue, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang, XJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wei, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Matsusaka, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yoshida, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sudo, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Naruto, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cell 77:63-71</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref45">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8140422</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhong, Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wen, Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 264:95-8</bp:SOURCE>
  </bp:publicationXref>
  <bp:control rdf:ID="control3">
    <bp:CONTROL-TYPE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">INHIBITION</bp:CONTROL-TYPE>
    <bp:XREF rdf:resource="#unificationXref71" />
    <bp:XREF rdf:resource="#unificationXref72" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:CONTROLLER rdf:resource="#physicalEntityParticipant44" />
    <bp:CONTROLLED rdf:resource="#biochemicalReaction12" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112775</bp:COMMENT>
  </bp:unificationXref>
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant44">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex13" />
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  <bp:complex rdf:ID="complex13">
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant45" />
    <bp:COMPONENTS rdf:resource="#sequenceParticipant20" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SOCS3 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SOCS3</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref74" />
    <bp:XREF rdf:resource="#unificationXref75" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant45">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112594</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant20">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein9" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature15" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 873794</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
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  <bp:protein rdf:ID="protein9">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:O14543 SOCS3</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SOCS3</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SOCS3</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CIS3</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SSI3</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including IL6ST/gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity and regulates IL6 signaling. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells (By similarity). Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:15601820).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with multiple activated proteins of the tyrosine kinase signaling pathway including IGF1 receptor, insulin receptor and JAK2. Binding to JAK2 is mediated through the KIR and SH2 domains to a phosphorylated tyrosine residue within the JAK2 JH1 domain (PubMed:10421843). Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors (PubMed:12027890, PubMed:14559241). Interaction with CSNK1E stabilizes SOCS3 protein (PubMed:15070676). Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SOCS3 (PubMed:15601820). Interacts with CUL5, RNF7, ELOB and ELOC (PubMed:15601820). Interacts with CUL2 (PubMed:15601820). Interacts with FGFR3 (PubMed:16410555). Interacts with INSR (By similarity). Interacts with BCL10; this interaction may interfere with BCL10-binding with PELI2 (By similarity). Interacts with NOD2 (via CARD domain); the interaction promotes NOD2 degradation (PubMed:23019338).TISSUE SPECIFICITY Widely expressed with high expression in heart, placenta, skeletal muscle, peripheral blood leukocytes, fetal and adult lung, and fetal liver and kidney. Lower levels in thymus.DOMAIN The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition.DOMAIN The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.PTM Phosphorylated on tyrosine residues after stimulation by the cytokines, IL-2, EPO or IGF1.DISEASE There is some evidence that SOCS3 may be a susceptibility gene for atopic dermatitis linked to 17q25. SOCS3 messenger RNA is significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls. Furthermore, a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene has been found in two independent groups of patients.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Serine phosphorylation of STATs</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:Tyrosine/serine phosphorylated STAT1/3 [plasma membrane]</bp:NAME>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2001</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The YXXQ motif in gp 130 is crucial for STAT3 phosphorylation at Ser727 through an H7-sensitive kinase pathway</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Abe, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hirai, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mizuno, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Higashi, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sekimoto, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Miki, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hirano, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nakajima, K</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oncogene 20:3464-74</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jain, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhang, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kee, WH</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li, W</bp:AUTHORS>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Biol Chem 274:24392-400</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2009</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT3 revs up the powerhouse</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reich, NC</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sci Signal 2:pe61</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1997</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wen, Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nucleic Acids Res 25:2062-7</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Shen, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schlessinger, K</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Meffre, E</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Quimby, F</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol Cell Biol 24:407-19</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chung, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Uchida, E</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blenis, J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol Cell Biol 17:6508-16</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Serine phosphorylation of STATs</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Decker, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kovarik, P</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oncogene 19:2628-37</bp:SOURCE>
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  <bp:pathwayStep rdf:ID="pathwayStep26">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction13" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction14">
    <bp:LEFT rdf:resource="#physicalEntityParticipant52" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant53" />
    <bp:RIGHT rdf:resource="#sequenceParticipant21" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylated STATs are released</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylated STATs are released</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref81" />
    <bp:XREF rdf:resource="#unificationXref82" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Following phosphorylation, STATs are released from the receptor.</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref45" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant52">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex12" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112524</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant53">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112594</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant21">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein8" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112571</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:unificationXref rdf:ID="unificationXref81">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112604</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112604</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref82">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112604</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">4</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112604.4</bp:COMMENT>
  </bp:unificationXref>
  <bp:pathwayStep rdf:ID="pathwayStep28">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction14" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep30" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction15">
    <bp:LEFT rdf:resource="#sequenceParticipant22" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant54" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylated STAT1, STAT3 form dimers</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Phosphorylated STAT1, STAT3 form dimers</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref83" />
    <bp:XREF rdf:resource="#unificationXref84" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref53" />
    <bp:XREF rdf:resource="#publicationXref37" />
    <bp:XREF rdf:resource="#publicationXref45" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant22">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein8" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112571</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">3</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant54">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity6" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112537</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntity rdf:ID="physicalEntity6">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">p-Y701-STAT1 dimer,p-Y705-STAT3 dimer,p-Y701-STAT1:p-Y705-STAT3 [cytosol]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:unificationXref rdf:ID="unificationXref83">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112538</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112538</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref84">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112538</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">3</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112538.3</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref53">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9630226</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1998</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chen, X</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Vinkemeier, U</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhao, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jeruzalmi, D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Darnell JE, Jr</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kuriyan, J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cell 93:827-39</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep30">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction15" />
    <bp:NEXT-STEP rdf:resource="#pathwayStep32" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction16">
    <bp:LEFT rdf:resource="#physicalEntityParticipant55" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant56" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT1 and STAT3 dimers translocate to the nucleus</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT1 and STAT3 dimers translocate to the nucleus</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref86" />
    <bp:XREF rdf:resource="#unificationXref87" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref37" />
    <bp:XREF rdf:resource="#publicationXref54" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant55">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity6" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112537</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant56">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity7" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112574</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:openControlledVocabulary rdf:ID="openControlledVocabulary5">
    <bp:TERM rdf:datatype="http://www.w3.org/2001/XMLSchema#string">nucleoplasm</bp:TERM>
    <bp:XREF rdf:resource="#unificationXref85" />
  </bp:openControlledVocabulary>
  <bp:unificationXref rdf:ID="unificationXref85">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">GO</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">0005654</bp:ID>
  </bp:unificationXref>
  <bp:physicalEntity rdf:ID="physicalEntity7">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">STAT1/3 homo and heterodimers [nucleoplasm]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:unificationXref rdf:ID="unificationXref86">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1112587</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=1112587</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref87">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-1112587</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">4</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1112587.4</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref54">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7701321</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1995</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Requirement of serine phosphorylation for formation of STAT-promoter complexes</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhang, X</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blenis, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Li, HC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schindler, Chris</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chen-Kiang, S</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 267:1990-4</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep32">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction16" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction17">
    <bp:LEFT rdf:resource="#physicalEntityParticipant57" />
    <bp:LEFT rdf:resource="#sequenceParticipant23" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant58" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11 binds p-Y759-IL6ST</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11 binds p-Y759-IL6ST</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SHP2 binds IL6ST phosphotyrosine-759</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref91" />
    <bp:XREF rdf:resource="#unificationXref92" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref55" />
    <bp:XREF rdf:resource="#publicationXref56" />
    <bp:XREF rdf:resource="#publicationXref38" />
    <bp:XREF rdf:resource="#publicationXref57" />
    <bp:XREF rdf:resource="#publicationXref58" />
    <bp:XREF rdf:resource="#publicationXref59" />
    <bp:XREF rdf:resource="#publicationXref60" />
    <bp:XREF rdf:resource="#publicationXref61" />
    <bp:XREF rdf:resource="#publicationXref62" />
    <bp:XREF rdf:resource="#publicationXref63" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant57">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1112594</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant23">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein10" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature16" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 162563</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein10">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:Q06124 PTPN11</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTP2C</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SHPTP2</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11</bp:SYNONYMS>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11 is phosphorylated</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">O4'-phospho-L-tyrosine at 542</bp:NAME>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2001</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lu, W</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gong, D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bar-Sagi, Dafna</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cole, PA</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol Cell 8:759-69</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SOCS3 binds IL6ST</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1998</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling</bp:TITLE>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Matsumoto, T</bp:AUTHORS>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Twenty proteins containing a C-terminal SOCS box form five structural classes</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, DJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Richardson, RT</bp:AUTHORS>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11 binds CBL</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PTPN11 binds CBL</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SHP2 binds c-Cbl upon IL-6 stimulation</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref103" />
    <bp:XREF rdf:resource="#unificationXref104" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">SHP2 binds CBL in response to IL-6 stimulation in 293T cells and contributes to the ubiquitination of gp130 (Tanaka et al. 2008).&lt;br&gt;
IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in its K63-linked polyubiquitination. 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. Deficiency of either Hrs or CBL suppressed gp130 degradation, leading to a prolonged and amplified IL-6 signal.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Ray, K, 2010-12-13</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Rose-John, S, 2011-02-11</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, S, 2010-12-10</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P22681 CBL</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CBL</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">RNF55</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CBL2</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:17094949). Ubiquitinates SPRY2 (PubMed:17094949, PubMed:17974561). Ubiquitinates EGFR (PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719). Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561). Interacts (phosphorylated at Tyr-774) with tensin TNS4 (via SH2 domain); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR (PubMed:23774213). Interacts with EGFR; the interaction is reduced in the presence of TNS4 (PubMed:23774213).SUBUNIT (Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.DOMAIN The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.DOMAIN The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.PTM Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK.PTM Ubiquitinated, leading to its degradation via the proteasome (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).MISCELLANEOUS This protein has one functional calcium-binding site.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:PTPN11:CBL [plasma membrane]</bp:NAME>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tanaka, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tanaka, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Saeki, Y</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Murakami, M</bp:AUTHORS>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol Cell Biol 28:4805-18</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The role of interleukin-6 signaling in nervous tissue</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rothaug, Michelle</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Becker-Pauly, Christoph</bp:AUTHORS>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2010</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Averting inflammation by targeting the cytokine environment</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kopf, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bachmann, MF</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Marsland, BJ</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nat Rev Drug Discov 9:703-18</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-6 and its receptors: a highly regulated and dynamic system</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wolf, Janina</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rose-John, Stefan</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Garbers, Christoph</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cytokine 70:11-20</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL-6: from its discovery to clinical applications</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Int Immunol 22:347-52</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL-6-type cytokine receptor ligand interactions</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The members involved in (interleukin)-6-type cytokine signalling are the IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CTF1) and cardiotrophin-like cytokine factor 1 (CLCF1). Receptors involved in recognition of the IL-6-type cytokines can be subdivided in the non-signalling alpha-receptors (IL6R, IL 11R, and CNTFR) and the signal transducing receptors (gp130, LIFR, and OSMR). The latter associate with JAKs and become tyrosine phosphorylated in response to cytokine stimulation (Heinrich et al. 1998, 2003). IL27 and IL35 belongs to IL12 cytokine family but they share gp130 as a component of signalling receptor, along with IL-6, IL-11, LIF, OSM, CNTF, CTF1 and CLCF1.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF binds CNTFR complex</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P26441 CNTF</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION CNTF is a survival factor for various neuronal cell types. Seems to prevent the degeneration of motor axons after axotomy.SUBUNIT Homodimer.TISSUE SPECIFICITY Nervous system.SIMILARITY Belongs to the CNTF family.</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Binds to CNTF. The alpha subunit provides the receptor specificity. Receptor for heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and IL27RA/WSX1 (PubMed:19386761).SUBUNIT Forms a heterotrimer with LIFR and IL6ST. Interacts with heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Either alone or in complex with the heterodimer CLCF1-CRLF1 interacts with SORL1; this interaction may promote internalization and lysosomal degradation (PubMed:26858303). Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin (PubMed:19386761).TISSUE SPECIFICITY Nervous system and skeletal muscle.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily.</bp:COMMENT>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stahl, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yancopoulos, G D</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Neurobiol. 25:1454-66</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Binding interactions of leukemia inhibitory factor and ciliary neurotrophic factor with the different subunits of their high affinity receptors</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Robledo, O</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Auguste, P</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Coupey, L</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Praloran, V</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pouplard, A</bp:AUTHORS>
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    <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, M W</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Anderson, K D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lambert, P D</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wiegand, S J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pharm Acta Helv 74:265-72</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1 binds CLCF1</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1 binds CLCF1</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:O75462 CRLF1</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UNQ288/PRO327</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). May also play a regulatory role in the immune system.SUBUNIT Forms covalent di- and tetramers. Forms a heteromeric complex with cardiotrophin-like cytokine CLCF1/CLC; the CRLF1-CLCF1 complex is a ligand for the ciliary neurotrophic factor receptor/CNTFR (PubMed:9686600, PubMed:26858303). The CRLF1-CLCF1 heterodimer binds SORL1 (via N-terminal ectodomain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety (PubMed:26858303). The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also binds SORL1 (PubMed:26858303).TISSUE SPECIFICITY Highest levels of expression observed in spleen, thymus, lymph node, appendix, bone marrow, stomach, placenta, heart, thyroid and ovary. Strongly expressed also in fetal lung.INDUCTION Up-regulated in fibroblast primary cell cultures under stimulation by IFNG/IFN-gamma, TNF and IL6/interleukin-6.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:Q9UBD9 CLCF1</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CLCF1</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">BSF3</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CLCF1</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). Also stimulates B-cells. Binds to and activates the ILST/gp130 receptor.SUBUNIT Forms a heteromeric complex with cardiotrophin-like cytokine CRLF1/CLF-1; the CRLF1-CLCF1 complex is a ligand for the ciliary neurotrophic factor receptor/CNTFR (PubMed:26858303). The CRLF1-CLCF1 heterodimer binds SORL1 (via N-terminal ectodomain); within this complex, the interaction is mediated predominantly by the CRLF1 moiety (PubMed:26858303). The tripartite signaling complex formed by CRLF1, CLCF1 and CNTFR also binds SORL1 (PubMed:26858303).TISSUE SPECIFICITY Expressed predominantly in lymph nodes, spleen, peripheral blood lymphocytes, bone marrow, and fetal liver.SIMILARITY Belongs to the IL-6 superfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1:CLCF1 [extracellular region]</bp:NAME>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2004</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)--a novel gp130 cytokine with pleiotropic functions</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Vlotides, George</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zitzmann, Kathrin</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stalla, Gunter K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Auernhammer, Christoph J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cytokine Growth Factor Rev. 15:325-36</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref81">
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Elson, G C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lelièvre, E</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guillet, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chevalier, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Plun-Favreau, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Froger, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Suard, I</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">de Coignac, A B</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Delneste, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bonnefoy, J Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gauchat, J F</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gascan, H</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nat. Neurosci. 3:867-72</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRLF1:CLCF1 binds CNTRF</bp:NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant74">
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  <bp:complex rdf:ID="complex20">
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yoshida, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Saito, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Suematsu, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kumanogoh, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tanaka, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Fujiwara, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hirata, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yamagami, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nakahata, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hirabayashi, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yoneda, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tanaka, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang, W Z</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mori, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Shiota, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yoshida, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Proc. Natl. Acad. Sci. U.S.A. 93:407-11</bp:SOURCE>
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    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11294841</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2001</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lelièvre, E</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Plun-Favreau, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chevalier, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Froger, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guillet, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Elson, G C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gauchat, J F</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gascan, H</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 276:22476-84</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref84">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18246092</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2008</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Fischer, P</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilfiker-Kleiner, D</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Br. J. Pharmacol. 153:S414-27</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref85">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21715184</bp:ID>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2011</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cytokine-like factor 1 (CLF1): life after development?</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kass, Daniel J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cytokine 55:325-9</bp:SOURCE>
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  <bp:pathwayStep rdf:ID="pathwayStep48">
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  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction24">
    <bp:LEFT rdf:resource="#physicalEntityParticipant76" />
    <bp:LEFT rdf:resource="#physicalEntityParticipant77" />
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">gp130:JAKs bind CNTFR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">gp130:JAKs bind CNTFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref125" />
    <bp:XREF rdf:resource="#unificationXref126" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant76">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1067690</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant77">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity8" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783659</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntity rdf:ID="physicalEntity8">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF:CNTFR,CRLF1:CLCF1:CNTFR [plasma membrane]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant78">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex21" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783658</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex21">
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant79" />
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant80" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF:CNTFR,CRLF1:CLCF1:CNTFR:IL6ST:JAK1, JAK2, (TYK2) [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF:CNTFR,CRLF1:CLCF1:CNTFR:IL6ST:JAK1, JAK2, (TYK2)</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref123" />
    <bp:XREF rdf:resource="#unificationXref124" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant79">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1067690</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant80">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity8" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783659</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:unificationXref rdf:ID="unificationXref123">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783658</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783658</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref124">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783658</bp:ID>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783658.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref125">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783530</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783530</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref126">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783530</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783530.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref86">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9143707</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1997</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gp130 and the interleukin-6 family of cytokines</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Annu. Rev. Immunol. 15:797-819</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref87">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">12707266</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2003</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Solution structure of the C-terminal domain of the ciliary neurotrophic factor (CNTF) receptor and ligand free associations among components of the CNTF receptor complex</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Man, David</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">He, Wei</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sze, Kong Hung</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gong, Ke</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Smith, David K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhu, Guang</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ip, Nancy Y</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 278:23285-94</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep50">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction24" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction25">
    <bp:LEFT rdf:resource="#sequenceParticipant39" />
    <bp:LEFT rdf:resource="#sequenceParticipant40" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant81" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs bind LIFR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs bind LIFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref130" />
    <bp:XREF rdf:resource="#unificationXref131" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref88" />
    <bp:XREF rdf:resource="#publicationXref7" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant39">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein16" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 5693181</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein16">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P42702 LIFR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref127" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Signal-transducing molecule. May have a common pathway with IL6ST. The soluble form inhibits the biological activity of LIF by blocking its binding to receptors on target cells.SUBUNIT Heterodimer composed of LIFR and IL6ST. The heterodimer formed by LIFR and IL6ST interacts with the complex formed by CNTF and CNTFR.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.DISEASE A chromosomal aberration involving LIFR is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(5;8)(p13;q12) with PLAG1.SIMILARITY Belongs to the type I cytokine receptor family. Type 2 subfamily.</bp:COMMENT>
  </bp:protein>
  <bp:unificationXref rdf:ID="unificationXref127">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">P42702</bp:ID>
  </bp:unificationXref>
  <bp:sequenceFeature rdf:ID="sequenceFeature34">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval32" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval32">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite65" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite66" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite65">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">45</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite66">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">1097</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant40">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein2" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1067656</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant81">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex22" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6784198</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex22">
    <bp:COMPONENTS rdf:resource="#sequenceParticipant41" />
    <bp:COMPONENTS rdf:resource="#sequenceParticipant42" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs:LIFR [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs:LIFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref128" />
    <bp:XREF rdf:resource="#unificationXref129" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant41">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein16" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature35" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 5693181</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:sequenceFeature rdf:ID="sequenceFeature35">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval33" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval33">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite67" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite68" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite67">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">45</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite68">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">1097</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant42">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein2" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 1067656</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:unificationXref rdf:ID="unificationXref128">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6784198</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6784198</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref129">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6784198</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6784198.1</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref130">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6784189</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6784189</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref131">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6784189</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6784189.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref88">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10586060</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1999</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to signal transduction in heterodimeric complexes with glycoprotein 130</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hermanns, H M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Radtke, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Haan, C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Schmitz-Van de Leur, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tavernier, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Behrmann, I</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Immunol. 163:6651-8</bp:SOURCE>
  </bp:publicationXref>
  <bp:pathwayStep rdf:ID="pathwayStep52">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction25" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction26">
    <bp:LEFT rdf:resource="#physicalEntityParticipant82" />
    <bp:LEFT rdf:resource="#physicalEntityParticipant83" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant84" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR:JAKs bind gp130:JAKs:CNTFR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR:JAKs bind gp130:JAKs:CNTFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref134" />
    <bp:XREF rdf:resource="#unificationXref135" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:XREF rdf:resource="#publicationXref92" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant83">
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    <bp:PHYSICAL-ENTITY rdf:resource="#complex21" />
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  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant84">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
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  <bp:complex rdf:ID="complex23">
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    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant86" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF:CNTFR,CRLF1:CLCF1:CNTFR:gp130:JAKs:LIFR:JAKs [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CNTF:CNTFR,CRLF1:CLCF1:CNTFR:gp130:JAKs:LIFR:JAKs</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref132" />
    <bp:XREF rdf:resource="#unificationXref133" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783556.2</bp:COMMENT>
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  <bp:publicationXref rdf:ID="publicationXref89">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8390097</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1993</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Davis, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Aldrich, T H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stahl, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pan, L</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ip, N Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yancopoulos, G D</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 260:1805-8</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref90">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11943154</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2002</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Membrane distal cytokine binding domain of LIFR interacts with soluble CNTFR in vitro</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">He, Wei</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gong, Ke</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Zhu, Guang</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Smith, David K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ip, Nancy Y</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FEBS Lett. 514:214-8</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref91">
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2005</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The N-terminal cytokine binding domain of LIFR is required for CNTF binding and signaling</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">He, Wei</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gong, Ke</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Smith, David K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ip, Nancy Y</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FEBS Lett. 579:4317-23</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref92">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9238703</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Expression of leukaemia inhibitory factor receptor subunits LIFR beta and gp130 in human oocytes and preimplantation embryos</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">van Eijk, M J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mandelbaum, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Salat-Baroux, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Belaisch-Allart, J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Plachot, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Junca, A M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mummery, C L</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol. Hum. Reprod. 2:355-60</bp:SOURCE>
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    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction26" />
  </bp:pathwayStep>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11 binds IL11RA</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11 binds IL11RA</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-11 receptor alpha chain binds Interleukin-11</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref140" />
    <bp:XREF rdf:resource="#unificationXref141" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Jupe, S, 2009-12-07</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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  <bp:protein rdf:ID="protein17">
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P20809 IL11</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref136" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Cytokine that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production (PubMed:2145578). Also promotes the proliferation of hepatocytes in response to liver damage. Binding to its receptor formed by IL6ST and IL11RA activates a signaling cascade that promotes cell proliferation (PubMed:12919066). Signaling leads to the activation of intracellular protein kinases and the phosphorylation of STAT3. The interaction with the membrane-bound IL11RA and IL6ST stimulates 'classic signaling', whereas the binding of IL11 and soluble IL11RA to IL6ST stimulates 'trans-signaling' (PubMed:30279168).SUBUNIT Interacts with IL11RA to associate with IL6ST, giving rise to a multimeric signaling complex.PHARMACEUTICAL Available under the name Neumega (Wyeth). Used for the prevention of severe thrombocytopenia and the reduction of the need for platelet transfusion following myelosuppressive chemotherapy.SIMILARITY Belongs to the IL-6 superfamily.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:Q14626 IL11RA</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11RA</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11RA</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref137" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Receptor for interleukin-11 (IL11). The receptor systems for IL6, LIF, OSM, CNTF, IL11 and CT1 can utilize IL6ST for initiating signal transmission. The IL11/IL11RA/IL6ST complex may be involved in the control of proliferation and/or differentiation of skeletogenic progenitor or other mesenchymal cells (Probable). Essential for the normal development of craniofacial bones and teeth. Restricts suture fusion and tooth number.SUBUNIT On IL11 binding, forms a multimer complex with IL6ST/gp130.TISSUE SPECIFICITY Expressed in a number of cell lines, including the myelogenous leukemia cell line K-562, the megakaryocytic leukemia cell line M-07e, the erythroleukemia cell line TF-1, and the osteosarcoma cell lines, MG-63 and SaOS-2 (PubMed:7670098). Also expressed in normal and malignant prostate epithelial cell lines. Expression levels are increased in prostate carcinoma.PTM A short soluble form is also released from the membrane by proteolysis (PubMed:26876177). The sIL11RA is formed either by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, or directly secreted from the cells after alternative mRNA splicing (PubMed:26876177). mIL11RA is cleaved by the proteases ADAM10, ELANE and PRTN3 (PubMed:26876177).SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily.</bp:COMMENT>
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    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Q14626</bp:ID>
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    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
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  <bp:complex rdf:ID="complex24">
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    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11RA:IL11 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11RA:IL11</bp:SHORT-NAME>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, DJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, AA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Raicevic, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rakar, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Harrison-Smith, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gough, NM</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Begley, CG</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Metcalf, D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nicola, NA</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Willson, TA</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EMBO J 13:4765-75</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref94">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">7670098</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1995</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Molecular cloning of two isoforms of a receptor for the human hematopoietic cytokine interleukin-11</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chérel, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sorel, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lebeau, B</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dubois, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Moreau, JF</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bataille, R</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Minvielle, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jacques, Y</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blood 86:2534-40</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref95">
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1993</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yin, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taga, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tsang, ML</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yasukawa, K</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kishimoto, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yang, YC</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J Immunol 151:2555-61</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref96">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9560294</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1998</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Activation of the signal transducer gp130 by interleukin-11 and interleukin-6 is mediated by similar molecular interactions</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dahmen, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Horsten, U</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Küster, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jacques, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Minvielle, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kerr, IM</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ciliberto, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Paonessa, G</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heinrich, PC</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Müller-Newen, G</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Biochem J 331:695-702</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL11:IL11RA binds IL6ST:JAK1,JAK2,(TYK2)</bp:NAME>
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    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interleukin-11 receptor alpha:Interleukin-11 binds Interleukin-6 receptor beta</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Jupe, S, 2009-12-07</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
  </bp:biochemicalReaction>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL6RA:IL6:IL6RB:JAKs [plasma membrane]</bp:NAME>
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  </bp:physicalEntityParticipant>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant92">
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=449948</bp:COMMENT>
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  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref97">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8637716</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1996</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">The human IL-11 receptor requires gp130 for signalling: demonstration by molecular cloning of the receptor</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nandurkar, HH</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, DJ</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nathan, P</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Willson, T</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nicola, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Begley, CG</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oncogene 12:585-93</bp:SOURCE>
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  <bp:pathwayStep rdf:ID="pathwayStep58">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction28" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction29">
    <bp:LEFT rdf:resource="#physicalEntityParticipant93" />
    <bp:LEFT rdf:resource="#sequenceParticipant47" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant94" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF binds LIFR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF binds LIFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref149" />
    <bp:XREF rdf:resource="#unificationXref150" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION LIF has the capacity to induce terminal differentiation in leukemic cells. Its activities include the induction of hematopoietic differentiation in normal and myeloid leukemia cells, the induction of neuronal cell differentiation, and the stimulation of acute-phase protein synthesis in hepatocytes.PHARMACEUTICAL In phase II clinical trial. The drug is being developed by Amrad to assist embryo implantation in women who have failed to become pregnant despite assisted reproductive technologies (ART).SIMILARITY Belongs to the LIF/OSM family.</bp:COMMENT>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF:LIFR:JAKs [plasma membrane]</bp:NAME>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1987</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF)</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gearing, D P</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gough, N M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">King, J A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, D J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nicola, N A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Simpson, R J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nice, E C</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kelso, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Metcalf, D</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EMBO J. 6:3995-4002</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1992</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Leukemia inhibitory factor--a puzzling polyfunctional regulator</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Metcalf, D</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Growth Factors 7:169-73</bp:SOURCE>
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    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1566332</bp:ID>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF: lots of interesting functions</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hilton, D J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Trends Biochem. Sci. 17:72-6</bp:SOURCE>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2002</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">N-CoR controls differentiation of neural stem cells into astrocytes</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hermanson, Ola</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jepsen, Kristen</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rosenfeld, Michael G</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nature 419:934-9</bp:SOURCE>
  </bp:publicationXref>
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    <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:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2003</bp:YEAR>
    <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, Juliette</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Daburon, Sophie</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Duplomb, Laurence</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Blanchard, Frédéric</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Vuisio, Patricia</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Jacques, Yannick</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Godard, Anne</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Heath, JK</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Moreau, Jean-François</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Taupin, Jean-Luc</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 278:16253-61</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF receptor signaling modulates neural stem cell renewal</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pitman, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Emery, B</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Binder, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang, S</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Butzkueven, H</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kilpatrick, T J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mol. Cell. Neurosci. 27:255-66</bp:SOURCE>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1997</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bonni, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Sun, Y</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nadal-Vicens, M</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bhatt, A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Frank, D A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rozovsky, I</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Stahl, N</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Yancopoulos, G D</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Greenberg, M E</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Science 278:477-83</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs bind OSMR</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs bind OSMR</bp:SHORT-NAME>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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).</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
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    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSMR</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Associates with IL31RA to form the IL31 receptor. Binds IL31 to activate STAT3 and possibly STAT1 and STAT5. Capable of transducing OSM-specific signaling events.SUBUNIT Heterodimer composed of OSMR and IL6ST (type II OSM receptor). Heterodimer with IL31RA to form the IL31 receptor.TISSUE SPECIFICITY Expressed in keratinocytes (at protein level) (PubMed:21261663). Expressed at relatively high levels in all neural cells as well as fibroblast and epithelial cells (PubMed:8999038).INDUCTION Activated by oncostatin-M (PubMed:8999038). Up-regulated by IFNG/IFN-gamma (PubMed:15184896, PubMed:21261663). Up-regulated by bacterial lipopolysaccharides (LPS) (PubMed:15184896). Up-regulated by triacylated lipoprotein (Pam3Cys) (PubMed:21261663).DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.SIMILARITY Belongs to the type I cytokine receptor family. Type 2 subfamily.</bp:COMMENT>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Q99650</bp:ID>
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    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs:OSMR [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAKs:OSMR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref152" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6784202</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6784202.1</bp:COMMENT>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6784204.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:pathwayStep rdf:ID="pathwayStep62">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction30" />
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  <bp:biochemicalReaction rdf:ID="biochemicalReaction31">
    <bp:LEFT rdf:resource="#sequenceParticipant53" />
    <bp:LEFT rdf:resource="#physicalEntityParticipant97" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant98" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM binds LIFR:JAKs,OSMR:JAKs</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM binds LIFR:JAKs,OSMR:JAKs</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref159" />
    <bp:XREF rdf:resource="#unificationXref160" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oncostatin M (OSM) is a multifunctional cytokine produced by bone microenvironment by cells of both mesenchymal and hematopoietic origin, including osteocytes, osteoblasts, macrophages and T lymphocytes (Brown et al. 1987, Malik et al. 1989). 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).</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref105" />
    <bp:XREF rdf:resource="#publicationXref106" />
    <bp:XREF rdf:resource="#publicationXref107" />
    <bp:XREF rdf:resource="#publicationXref108" />
    <bp:XREF rdf:resource="#publicationXref109" />
    <bp:XREF rdf:resource="#publicationXref110" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant53">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary4" />
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  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein21">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P13725 OSM</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref156" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Growth regulator. Inhibits the proliferation of a number of tumor cell lines. Stimulates proliferation of AIDS-KS cells. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells. Uses both type I OSM receptor (heterodimers composed of LIFR and IL6ST) and type II OSM receptor (heterodimers composed of OSMR and IL6ST). Involved in the maturation of fetal hepatocytes, thereby promoting liver development and regeneration (By similarity).PTM Propeptide processing is not important for receptor binding activity but may be important growth-inhibitory activity.SIMILARITY Belongs to the LIF/OSM family.</bp:COMMENT>
  </bp:protein>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">P13725</bp:ID>
  </bp:unificationXref>
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  </bp:sequenceSite>
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  </bp:sequenceSite>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity9" />
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  </bp:physicalEntityParticipant>
  <bp:physicalEntity rdf:ID="physicalEntity9">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIFR:JAKs,OSMR:JAKs [plasma membrane]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant98">
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    <bp:PHYSICAL-ENTITY rdf:resource="#complex28" />
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    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex28">
    <bp:COMPONENTS rdf:resource="#sequenceParticipant54" />
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant99" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM:OSMR,LIFR [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM:OSMR,LIFR</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref157" />
    <bp:XREF rdf:resource="#unificationXref158" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
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    <bp:PHYSICAL-ENTITY rdf:resource="#protein21" />
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 5696440</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:sequenceFeature rdf:ID="sequenceFeature45">
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  </bp:sequenceFeature>
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  </bp:sequenceInterval>
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    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant99">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity9" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783627</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
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    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783585</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783585</bp:COMMENT>
  </bp:unificationXref>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783585</bp:ID>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783585.1</bp:COMMENT>
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    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783552</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783552</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref160">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783552</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783552.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:publicationXref rdf:ID="publicationXref105">
    <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:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1994</bp:YEAR>
    <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</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bird, T A</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Friend, D J</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gearing, D P</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dower, S K</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 269:6215-22</bp:SOURCE>
  </bp:publicationXref>
  <bp:publicationXref rdf:ID="publicationXref106">
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10579456</bp:ID>
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Pubmed</bp:DB>
    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">1999</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Oncostatin M: signal transduction and biological activity</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gómez-Lechón, M J</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Life Sci. 65:2019-30</bp:SOURCE>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM,LIF,CTF1 receptor complex binds gp130</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSM,LIF,CTF1 receptor complex binds gp130</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref168" />
    <bp:XREF rdf:resource="#unificationXref169" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref108" />
    <bp:XREF rdf:resource="#publicationXref103" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Narazaki, M, Tanaka, M, 2015-11-09</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Garapati, Phani Vijay, 2015-07-21</bp:COMMENT>
  </bp:biochemicalReaction>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 448453</bp:COMMENT>
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    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite93" />
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    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">23</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
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  <bp:sequenceSite rdf:ID="sequenceSite94">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">918</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant103">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity10" />
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  <bp:physicalEntity rdf:ID="physicalEntity10">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF,OSM,CTF1 receptor complex [plasma membrane]</bp:NAME>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity</bp:COMMENT>
  </bp:physicalEntity>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant104">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex30" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783569</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex30">
    <bp:COMPONENTS rdf:resource="#sequenceParticipant58" />
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant105" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF,OSM receptor complex:gp130 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">LIF,OSM receptor complex:gp130</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref166" />
    <bp:XREF rdf:resource="#unificationXref167" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant58">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein1" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature49" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 448453</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:sequenceFeature rdf:ID="sequenceFeature49">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval47" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval47">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite95" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite96" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite95">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">23</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite96">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">918</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant105">
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Converted from EntitySet in Reactome</bp:COMMENT>
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#physicalEntity10" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 6783699</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:unificationXref rdf:ID="unificationXref166">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783569</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783569</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref167">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783569</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">1</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783569.1</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref168">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome Database ID Release 85</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">6783524</bp:ID>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&amp;ID=6783524</bp:COMMENT>
  </bp:unificationXref>
  <bp:unificationXref rdf:ID="unificationXref169">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">R-HSA-6783524</bp:ID>
    <bp:ID-VERSION rdf:datatype="http://www.w3.org/2001/XMLSchema#string">2</bp:ID-VERSION>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6783524.2</bp:COMMENT>
  </bp:unificationXref>
  <bp:pathwayStep rdf:ID="pathwayStep68">
    <bp:STEP-INTERACTIONS rdf:resource="#biochemicalReaction33" />
  </bp:pathwayStep>
  <bp:biochemicalReaction rdf:ID="biochemicalReaction34">
    <bp:LEFT rdf:resource="#physicalEntityParticipant106" />
    <bp:LEFT rdf:resource="#physicalEntityParticipant108" />
    <bp:RIGHT rdf:resource="#physicalEntityParticipant109" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31:IL31RA:JAK1 binds OSMR:JAK1</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31:IL31RA:JAK1 binds OSMR:JAK1</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref180" />
    <bp:XREF rdf:resource="#unificationXref181" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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). As the pre-association of IL31RA with JAK1 is unproven this event is represented as a black-box.</bp:COMMENT>
    <bp:XREF rdf:resource="#publicationXref115" />
    <bp:XREF rdf:resource="#publicationXref116" />
    <bp:XREF rdf:resource="#publicationXref117" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Authored: Jupe, Steve, 2014-06-04</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reviewed: Meldal, Birgit, 2016-01-28</bp:COMMENT>
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Edited: Jupe, Steve, 2016-01-28</bp:COMMENT>
  </bp:biochemicalReaction>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant106">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex31" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 8983441</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex31">
    <bp:COMPONENTS rdf:resource="#sequenceParticipant59" />
    <bp:COMPONENTS rdf:resource="#physicalEntityParticipant107" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31:IL31RA:JAK1 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31:IL31RA:JAK1</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref174" />
    <bp:XREF rdf:resource="#unificationXref175" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant59">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary4" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein23" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature50" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 448651</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein23">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:Q6EBC2 IL31</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref170" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Activates STAT3 and possibly STAT1 and STAT5 through the IL31 heterodimeric receptor composed of IL31RA and OSMR (PubMed:15184896). May function in skin immunity (PubMed:15184896). Enhances myeloid progenitor cell survival in vitro (By similarity). Induces RETNLA and serum amyloid A protein expression in macrophages (By similarity).TISSUE SPECIFICITY Detected at low levels in testis, bone marrow, skeletal muscle, kidney, colon, thymus, small intestine and trachea.INDUCTION Up-regulated in skin homing T-cells of patients with atopic dermatitis (AD) and in activated circulating T-cells. Up-regulated in lesional biopsies of patients with allergic contact dermatitis (ACD).</bp:COMMENT>
  </bp:protein>
  <bp:unificationXref rdf:ID="unificationXref170">
    <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt</bp:DB>
    <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Q6EBC2</bp:ID>
  </bp:unificationXref>
  <bp:sequenceFeature rdf:ID="sequenceFeature50">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
    <bp:FEATURE-LOCATION rdf:resource="#sequenceInterval48" />
  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval48">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite97" />
    <bp:SEQUENCE-INTERVAL-END rdf:resource="#sequenceSite98" />
  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite97">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">24</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite98">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">164</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:physicalEntityParticipant rdf:ID="physicalEntityParticipant107">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#complex32" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 8983439</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:physicalEntityParticipant>
  <bp:complex rdf:ID="complex32">
    <bp:COMPONENTS rdf:resource="#sequenceParticipant60" />
    <bp:COMPONENTS rdf:resource="#sequenceParticipant61" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31RA:JAK1 [plasma membrane]</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31RA:JAK1</bp:SHORT-NAME>
    <bp:XREF rdf:resource="#unificationXref172" />
    <bp:XREF rdf:resource="#unificationXref173" />
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
  </bp:complex>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant60">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary3" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein24" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature51" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 451898</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein24">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:P23458 JAK1</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1B</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1A</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">JAK1</bp:SYNONYMS>
    <bp:XREF rdf:resource="#unificationXref6" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:8232552, PubMed:7615558, PubMed:28111307, PubMed:32750333, PubMed:16239216). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952). Kinase partner for the type I interferon receptor IFNAR2 (PubMed:8232552, PubMed:7615558, PubMed:28111307, PubMed:32750333, PubMed:16239216). In response to interferon-binding to IFNAR1-IFNAR2 heterodimer, phosphorylates and activates its binding partner IFNAR2, creating docking sites for STAT proteins (PubMed:7759950). Directly phosphorylates STAT proteins but also activates STAT signaling through the transactivation of other JAK kinases associated with signaling receptors (PubMed:8232552, PubMed:16239216, PubMed:32750333).SUBUNIT Interacts with IL31RA (PubMed:15194700). Interacts with IFNGR1 (PubMed:7615558). Interacts with JAKMIP1 (PubMed:15277531). Interacts with SHB (PubMed:12200137). Interacts (via N-terminus) with IL2RB and IL10RA (via its cytoplasmic domain) (PubMed:12133952). Interacts with FER (By similarity).TISSUE SPECIFICITY Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.DOMAIN The protein kinase 1 domain is also called the pseudokinase domain and has a regulatory role through the transactivation of other JAK kinases associated with signaling receptors.DOMAIN The protein kinase 2 domain is the catalytically active domain.DOMAIN The FERM domain mediates interaction with JAKMIP1.PTM Autophosphorylated (PubMed:7615558). Phosphorylated by TYK2 on tyrosine residues in response to type-I interferon signaling, leading to its activation (PubMed:8232552). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558). Dephosphorylation of Tyr-1034 and Tyr-1035 by PTPN2 negatively regulates cytokine-mediated signaling (PubMed:11909529).PTM Ubiquitinated by RNF125; leading to its degradation by the proteasome.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.</bp:COMMENT>
  </bp:protein>
  <bp:sequenceFeature rdf:ID="sequenceFeature51">
    <bp:FEATURE-TYPE rdf:resource="#openControlledVocabulary2" />
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  </bp:sequenceFeature>
  <bp:sequenceInterval rdf:ID="sequenceInterval49">
    <bp:SEQUENCE-INTERVAL-BEGIN rdf:resource="#sequenceSite99" />
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  </bp:sequenceInterval>
  <bp:sequenceSite rdf:ID="sequenceSite99">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">1</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceSite rdf:ID="sequenceSite100">
    <bp:SEQUENCE-POSITION rdf:datatype="http://www.w3.org/2001/XMLSchema#integer">1154</bp:SEQUENCE-POSITION>
    <bp:POSITION-STATUS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">EQUAL</bp:POSITION-STATUS>
  </bp:sequenceSite>
  <bp:sequenceParticipant rdf:ID="sequenceParticipant61">
    <bp:CELLULAR-LOCATION rdf:resource="#openControlledVocabulary1" />
    <bp:PHYSICAL-ENTITY rdf:resource="#protein25" />
    <bp:SEQUENCE-FEATURE-LIST rdf:resource="#sequenceFeature52" />
    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactome DB_ID: 448612</bp:COMMENT>
    <bp:STOICHIOMETRIC-COEFFICIENT rdf:datatype="http://www.w3.org/2001/XMLSchema#double">1</bp:STOICHIOMETRIC-COEFFICIENT>
  </bp:sequenceParticipant>
  <bp:protein rdf:ID="protein25">
    <bp:DATA-SOURCE rdf:resource="#dataSource1" />
    <bp:ORGANISM rdf:resource="#bioSource1" />
    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UniProt:Q8NI17 IL31RA</bp:NAME>
    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31RA</bp:SHORT-NAME>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">GPL</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31RA</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">CRL3</bp:SYNONYMS>
    <bp:SYNONYMS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">UNQ6368/PRO21073/PRO21384</bp:SYNONYMS>
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    <bp:COMMENT rdf:datatype="http://www.w3.org/2001/XMLSchema#string">FUNCTION Associates with OSMR to form the interleukin-31 receptor which activates STAT3 and to a lower extent STAT1 and STAT5 (PubMed:11877449, PubMed:14504285, PubMed:15627637, PubMed:15194700). May function in skin immunity (PubMed:15184896). Mediates IL31-induced itch, probably in a manner dependent on cation channels TRPA1 and TRPV1 (By similarity). Positively regulates numbers and cycling status of immature subsets of myeloid progenitor cells in bone marrow in vivo and enhances myeloid progenitor cell survival in vitro (By similarity).SUBUNIT Heterodimer with OSMR. Interacts with JAK1 and STAT3.TISSUE SPECIFICITY Expressed in CD14- and CD56-positive blood cells (PubMed:11877449). Expressed in macrophages (PubMed:16461143, PubMed:18439099). Expressed in keratinocytes (PubMed:21261663). Expressed in a subset of dorsal root ganglia neurons (at protein level) (PubMed:24373353). Expressed at low levels in testis, ovary, brain, prostate, placenta, thymus, bone marrow, trachea and skin (PubMed:15184896, PubMed:11877449, PubMed:14504285). Expressed in bronchial and alveolar epithelial cells and pulmonary fibroblasts (PubMed:18439099). Detected in all of the myelomonocytic lineage (PubMed:14504285). Isoform 6: Expressed at higher levels in lesional skin compared to healthy skin of atopic dermatitis patients (PubMed:24373353).INDUCTION Up-regulated in lesional keratinocytes of patients with atopic dermatitis (PubMed:16461143). Up-regulated by IFNG/IFN-gamma (PubMed:11877449, PubMed:14504285, PubMed:15184896, PubMed:21261663, PubMed:18439099). Up-regulated by bacterial lipopolysaccharides (LPS) (PubMed:11877449, PubMed:15184896, PubMed:14504285). Up-regulated by triacylated lipoprotein (Pam3Cys) (PubMed:21261663). Up-regulated by TGFB1/TGF-beta (PubMed:18439099).PTM N-glycosylated.SIMILARITY Belongs to the type I cytokine receptor family. Type 2 subfamily.</bp:COMMENT>
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    <bp:SHORT-NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">OSMR:JAK1</bp:SHORT-NAME>
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    <bp:NAME rdf:datatype="http://www.w3.org/2001/XMLSchema#string">IL31:IL31RA:JAK1:OSMR:JAK1 [plasma membrane]</bp:NAME>
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2010</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Molecular dissection of human interleukin-31-mediated signal transduction through site-directed mutagenesis</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Le Saux, Sabine</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rousseau, François</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Barbier, Fabien</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ravon, Elisa</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Grimaud, Linda</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Danger, Yannic</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Froger, Josy</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chevalier, Sylvie</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gascan, Hugues</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 285:3470-7</bp:SOURCE>
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  <bp:publicationXref rdf:ID="publicationXref116">
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    <bp:YEAR rdf:datatype="http://www.w3.org/2001/XMLSchema#int">2004</bp:YEAR>
    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Diveu, Caroline</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lak-Hal, Anne-Hélène Lagrue</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Froger, Josy</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Barbier, Fabien</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hermann, Jacques</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Gascan, Hugues</bp:AUTHORS>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Chevalier, Sylvie</bp:AUTHORS>
    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Eur. Cytokine Netw. 15:291-302</bp:SOURCE>
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    <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Prerequisites for Functional Interleukin 31 Signaling and Its Feedback Regulation by Suppressor of Cytokine Signaling 3 (SOCS3)</bp:TITLE>
    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Maier, Elisabeth</bp:AUTHORS>
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    <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Neuper, Theresa</bp:AUTHORS>
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    <bp:SOURCE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">J. Biol. Chem. 290:24747-59</bp:SOURCE>
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