BioPAX pathway converted from "IL35 binds IL6ST:IL6ST receptor" in the Reactome database. LEFT-TO-RIGHT IL35 binds IL6ST:IL6ST receptor Interleukin-35 (IL35) is a heteromeric complex conformed by Interleukin-12 subunit alpha (IL12A) and Interleukin-27 subunit alpha (IL27). IL35 can stimulate Janus Kinase (JAK)-bound homodimers of Interleukin-6 receptor beta precursor (IL6ST or gp130). JAKs are believed to be associated with the receptor before receptor activation (Behrmann et al., 2004). Subsequently, this triggers the phosphorylation of STAT1 downstream. The physiological consequence of this signalling is the suppression of T-cell response. The event is represented as a black box due to the incomplete knowledge about the ligand binding to monomers followed by dimerization or binding directly to the dimers. Authored: Varusai, Thawfeek, 2016-12-15 Reviewed: Singh, Kailash, 2017-07-05 Reviewed: Pylayeva-Gupta, Yuliya, 2017-08-09 Edited: Varusai, Thawfeek, 2016-12-15 IL6ST:JAK1, JAK2, (TYK2) Reactome DB_ID: 1067690 plasma membrane GENE ONTOLOGY GO:0005886 Converted from EntitySet in Reactome JAK1, JAK2, (TYK2) Reactome DB_ID: 1067656 JAK1 Tyrosine-protein kinase JAK1 JAK1_HUMAN Janus kinase 1 Reactome DB_ID: 451898 cytosol GENE ONTOLOGY GO:0005829 UniProt:P23458 JAK1 JAK1 JAK1A JAK1B FUNCTION Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:7615558). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952).SUBUNIT Interacts with IL31RA (PubMed:15194700). Interacts with IFNAR2 (PubMed:7759950). 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 Possesses two phosphotransferase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for domain 1.DOMAIN The FERM domain mediates interaction with JAKMIP1.PTM Autophosphorylated (PubMed:7615558). 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. Homo sapiens NCBI Taxonomy 9606 UniProt P23458 1 EQUAL 1154 EQUAL Reactome Database ID Release 77 451898 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=451898 Reactome R-HSA-451898 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451898.2 Reactome //www.joaskin.com JAK2 Tyrosine-protein kinase JAK2 Reactome DB_ID: 210620 UniProt:O60674 JAK2 JAK2 函数Non-receptor酪氨酸激酶参与various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980).ACTIVITY REGULATION Regulated by autophosphorylation, can both activate or decrease activity (By similarity). Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr-1008 (PubMed:21036157).SUBUNIT Interacts with EPOR, LYN, SIRPA, SH2B1 and TEC (By similarity). Interacts with IL23R (PubMed:12023369). Interacts with SKB1 (PubMed:10531356). Interacts with STAM2 (PubMed:10899310). Interacts with IFNGR2 (via intracellular domain) (PubMed:7673114, PubMed:7615558). Interacts with LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with STRA6 (PubMed:21368206). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874).TISSUE SPECIFICITY Ubiquitously expressed throughout most tissues.DOMAIN Possesses 2 protein kinase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for protein kinase 1 (By similarity).PTM Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 (By similarity). Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity (By similarity). Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (By similarity). Also phosphorylated by TEC (By similarity). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558, PubMed:7673114). Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (PubMed:21368206).DISEASE Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. UniProt O60674 1 EQUAL 1132 EQUAL Reactome Database ID Release 77 210620 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=210620 Reactome R-HSA-210620 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210620.2 TYK2 Non-receptor tyrosine-protein kinase TYK2 TYK2_HUMAN Reactome DB_ID: 877348 UniProt:P29597 TYK2 TYK2 FUNCTION Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.SUBUNIT Interacts with JAKMIP1.TISSUE SPECIFICITY Observed in all cell lines analyzed. Expressed in a variety of lymphoid and non-lymphoid cell lines.DOMAIN The FERM domain mediates interaction with JAKMIP1.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. UniProt P29597 1 EQUAL 1187 EQUAL Reactome Database ID Release 77 877348 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=877348 Reactome R-HSA-877348 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-877348.1 Reactome Database ID Release 77 1067656 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=1067656 Reactome R-HSA-1067656 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1067656.2 1 IL6ST IL6RB Interleukin-6 receptor subunit beta IL6RB_HUMAN GP130 Reactome DB_ID: 448453 UniProt:P40189 IL6ST IL6ST 函数Signal-transducing分子(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 activate 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). 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). 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. UniProt P40189 23 EQUAL 918 EQUAL Reactome Database ID Release 77 448453 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=448453 Reactome R-HSA-448453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-448453.1 1 Reactome Database ID Release 77 1067690 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=1067690 Reactome R-HSA-1067690 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1067690.2 2 IL35 Interleukin-35 IL12A:EBI3 Reactome DB_ID: 622267 extracellular region GENE ONTOLOGY GO:0005576 EBI3 Epstein-Barr virus-induced gene 3 protein IL27B_HUMAN IL27B Interleukin-27 subunit beta Reactome DB_ID: 448418 UniProt:Q14213 EBI3 EBI3 IL27B 函数与IL27 Associates形成IL-27terleukin, a heterodimeric cytokine which functions in innate immunity. IL-27 has pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells. Among its target cells are CD4 T-helper cells which can differentiate in type 1 effector cells (TH1), type 2 effector cells (TH2) and IL17 producing helper T-cells (TH17). It drives rapid clonal expansion of naive but not memory CD4 T-cells. It also strongly synergizes with IL-12 to trigger interferon-gamma/IFN-gamma production of naive CD4 T-cells, binds to the cytokine receptor WSX-1/TCCR. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines.SUBUNIT Heterodimer with IL27/IL27A; not disulfide-linked (PubMed:12121660). This heterodimer is known as interleukin IL-27 (PubMed:12121660). Heterodimer with IL12A; not disulfide-linked (PubMed:9342359). This heterodimer is known as interleukin IL-35 (PubMed:9342359). Interacts with SQSTM1 (PubMed:8551575).INDUCTION By Epstein-Barr virus (EBV).SIMILARITY Belongs to the type I cytokine receptor family. Type 3 subfamily. UniProt Q14213 21 EQUAL 229 EQUAL Reactome Database ID Release 77 448418 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=448418 Reactome R-HSA-448418 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-448418.2 1 IL12A IL12p35 IL12-p35 Interleukin-12 subunit alpha IL12A_HUMAN Reactome DB_ID: 447212 UniProt:P29459 IL12A IL12A NKSF1 FUNCTION Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC.SUBUNIT Heterodimer with IL12B; disulfide-linked (PubMed:1674604, PubMed:10899108). This heterodimer is known as interleukin IL-12 (PubMed:1674604). Heterodimer with EBI3/IL27B; not disulfide-linked (PubMed:9342359). This heterodimer is known as interleukin IL-35 (PubMed:9342359).INDUCTION (Microbial infection) Down-regulated in response to enterovirus 71 (EV71) infection.SIMILARITY Belongs to the IL-6 superfamily. UniProt P29459 23 EQUAL 219 EQUAL Reactome Database ID Release 77 447212 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=447212 Reactome R-HSA-447212 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-447212.2 1 Reactome Database ID Release 77 622267 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=622267 Reactome R-HSA-622267 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-622267.3 IL-35:(IL6ST:JAK1:JAK2) dimer Reactome DB_ID: 8983525 2 1 Reactome Database ID Release 77 8983525 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=8983525 Reactome R-HSA-8983525 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983525.1 Reactome Database ID Release 77 8983518 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=8983518 Reactome R-HSA-8983518 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8983518.1 15123646 Pubmed 2004 Janus激酶(激酶)的亚细胞定位revisited: the exclusive membrane localization of endogenous Janus kinase 1 by cytokine receptor interaction uncovers the Jak.receptor complex to be equivalent to a receptor tyrosine kinase Behrmann, Iris Smyczek, Tanja Heinrich, Peter C Schmitz-Van De Leur, Hildegard Komyod, Waraporn Giese, Bernd Müller-Newen, Gerhard Haan, Serge Haan, Claude J. Biol. Chem. 279:35486-93 22306691 Pubmed 2012 The composition and signaling of the IL-35 receptor are unconventional Collison, Lauren W Delgoffe, Greg M Guy, Clifford S Vignali, Kate M Chaturvedi, Vandana Fairweather, DeLisa Satoskar, Abhay R Garcia, K Christopher Hunter, Christopher A Drake, Charles G Murray, Peter J Vignali, Dario A A Nat. Immunol. 13:290-9 12829785 Pubmed 2003 Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex 面包师,乔丹 Chow, DC Brevnova, EE Garcia, KC Science 300:2101-4