BioPAX pathway converted from "CTF1 binds LIFR:JAKs" in the Reactome database.LEFT-TO-RIGHTCTF1 binds LIFR:JAKsCardiotrophin-1 (CTF1/CT-1) is a member of the IL-6 family of cytokines which was originally discovered as a factor which can induce hypertrophy of cardiac myocytes both in vitro and in vivo (Pennica et al. 1995a). Subsequently, CTF1 has been shown to have a wide variety of different effects on cardiac and non cardiac cells including the ability to stimulate the survival of both cardiac and neuronal cells (Latchman 1999). Leukemia inhibitory factor (LIF), CTF1, and oncostatin M (OSM) are four helix bundle cytokines acting through a common heterodimeric receptor composed of gp130 and LIF receptor (LIFR) (Pennica et al. 1995b).Authored: Garapati, Phani Vijay, 2015-07-21Reviewed: Narazaki, M, Tanaka, M, 2015-11-09Edited: Garapati, Phani Vijay, 2015-07-21CTF1Cardiotrophin-1CTF1_HUMANReactome DB_ID: 5696437extracellular regionGENE ONTOLOGYGO:0005576UniProt:Q16619 CTF1CTF1FUNCTION Induces cardiac myocyte hypertrophy in vitro. Binds to and activates the ILST/gp130 receptor.TISSUE SPECIFICITY Highly expressed in heart, skeletal muscle, prostate and ovary. Lower levels in lung, kidney, pancreas, thymus, testis and small intestine. Little or no expression in brain, placenta, liver, spleen, colon or peripheral blood leukocytes.SIMILARITY Belongs to the IL-6 superfamily.Homo sapiensNCBI Taxonomy9606UniProtQ166191EQUAL201EQUALReactome Database ID Release 755696437Database 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&ID=5696437ReactomeR-HSA-56964371Reactome 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-5696437.1Reactomehttp://www.reactome.orgJAKs:LIFRReactome DB_ID: 6784198plasma membraneGENE ONTOLOGYGO:0005886Converted from EntitySet in ReactomeJAK1, JAK2, (TYK2)Reactome DB_ID: 1067656JAK1Tyrosine-protein kinase JAK1JAK1_HUMANJanus kinase 1Reactome DB_ID: 451898cytosolGENE ONTOLOGYGO:0005829UniProt:P23458 JAK1JAK1JAK1AJAK1BFUNCTION 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.UniProtP234581EQUAL1154EQUALReactome Database ID Release 75451898Database 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&ID=451898ReactomeR-HSA-4518982Reactome 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-451898.2JAK2Tyrosine-protein kinase JAK2Reactome DB_ID: 210620UniProt:O60674 JAK2JAK2FUNCTION Non-receptor tyrosine kinase involved in 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.UniProtO606741EQUAL1132EQUALReactome Database ID Release 75210620Database 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&ID=210620ReactomeR-HSA-2106202Reactome 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-210620.2TYK2Non-receptor tyrosine-protein kinase TYK2TYK2_HUMANReactome DB_ID: 877348UniProt:P29597 TYK2TYK2FUNCTION 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.UniProtP295971EQUAL1187EQUALReactome Database ID Release 75877348Database 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&ID=877348ReactomeR-HSA-8773481Reactome 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-877348.1Reactome Database ID Release 751067656Database 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&ID=1067656ReactomeR-HSA-10676562Reactome 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-1067656.21LIFRLeukemia inhibitory factor receptorLIFR_HUMANReactome DB_ID: 5693181UniProt:P42702 LIFRLIFRFUNCTION 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.UniProtP4270245EQUAL1097EQUALReactome Database ID Release 755693181Database 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&ID=5693181ReactomeR-HSA-56931811Reactome 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-5693181.11Reactome Database ID Release 756784198Database 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&ID=6784198ReactomeR-HSA-67841981Reactome 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-6784198.1CTF1:LIFR:JAKsReactome DB_ID: 678353311Reactome Database ID Release 756783533Database 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&ID=6783533ReactomeR-HSA-67835331Reactome 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-6783533.1Reactome Database ID Release 755696482Database 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&ID=5696482ReactomeR-HSA-56964821Reactome 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-5696482.17862649Pubmed1995Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophyPennica, DKing, K LShaw, K JLuis, ERullamas, JLuoh, S MDarbonne, W CKnutzon, D SYen, RChien, K RProc. Natl. Acad. Sci. U.S.A. 92:1142-67738033Pubmed1995Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complexPennica, DShaw, K JSwanson, T AMoore, M WShelton, D LZioncheck, K ARosenthal, ATaga, TPaoni, N FWood, W IJ. Biol. Chem. 270:10915-2211834704Pubmed2002Cardiotrophin-1 stimulation of cardiac fibroblast growth: roles for glycoprotein 130/leukemia inhibitory factor receptor and the endothelin type A receptorTsuruda, ToshihiroJougasaki, MichihisaBoerrigter, GuidoHuntley, Brenda KChen, Horng HD'Assoro, Antonino BLee, Shang CLarsen, Amy MCataliotti, AlessandroBurnett, John CCirc. Res. 90:128-3410583628Pubmed1999Cardiotrophin-1 (CT-1): a novel hypertrophic and cardioprotective agentLatchman, D SInt J Exp Pathol 80:189-96