Interleukin-4 and Interleukin-13 signaling (Homo sapiens)

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4, 129, 44183, 25, 39, 50, 63...9280, 955, 54, 924814, 27, 6419, 251, 224197, 15, 25, 26, 30...453810, 53, 98, 99549814217, 87698, 25, 31, 56, 63...21, 47, 49, 78, 8425, 75, 889813, 595423, 54, 67, 73, 9325, 339254, 9229, 545417, 28, 43, 87, 9952, 546951549, 442, 11, 20, 24, 25, 32...6, 764151916, 34, 459cytosolendoplasmic reticulum lumennucleoplasmmitochondrial matrixHMOX1 geneTP53 gene JAK2 IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6HGF gene p-Y705-STAT3 p-Y-IL4R FOXO3 TNFRSF1B gene IL1A gene IL6 ITGAX IL12B gene ZEB1 gene MYC gene ADPIL4,IL13-downregulated extracellular proteinsIL18 gene p-Y701-STAT1 IL2RG IL13-boundtyrosine-phosphorylated IL13 receptor type II with phosphorylated STAT1,STAT3,STAT64xPalmC-CD36JAK2 TNF gene IL4:IL4R:JAK2:IL2RG:JAK3RORC gene Myr82K-Myr83K-IL1A JAK3 IRF4 gene TNF gene p-Y701-STAT1 HSP90AA1 TYK2IL13RA1 STAT6 JAK3 STAT6 IL4:IL4R:JAK2IL17A IL23R gene TNF(77-233) CCND1 gene BIRC5 gene IL17F gene p-Y705-STAT3 dimer,p-Y641-STAT6 dimerJAK1SAA1(19-122) JUNB gene p-Y-JAK1 POMC gene p-Y-IL4R PTGS2ATPp-Y705-STAT3 SAA1 gene VCAM1 gene RORA p-Y641-STAT6 IL13-boundtyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6JAK2 IL13-downregulatedgenes forextracellularproteinsTYK2 HIF1A S1PR1 gene BCL6 gene p-Y701-STAT1 SOCS1CDKN1A CCL11 gene OSM gene IL4,IL13-upregulatedextracellularproteinsJAK1 factor XIII A chain ITGB1 IL4R:JAK2IL6 gene HSP90AA1 gene OSM IL13RA2 IL13 TIMP1 gene OPRD1 IGHG1 gene CCL11 ALOX15 AKT1 gene NANOG IL12A IL13-upregulatedproteinsVEGFA IL4 TP53 IL2RG:JAK3p-Y1007-JAK2 JAK1 ITGB1 Gene PIM1 STAT1 FOXO1 gene IL13:IL13RA2p-Y641-STAT6 IL6 gene ADPp-Y-IL4R JAK3LBP IL4 p-Y1007-JAK2 NOS2 ATPHSPA8 gene HSP90B1MUC1(24-1255) FASLG(1-281)BIRC5 PIK3R1 gene STAT6 upregulatedextracellularproteinsRHOU gene p-Y-IL13RA1 CEBPD gene COL1A2 p-Y641-STAT6 dimerGATA3 geneMAOATGFB1(30-278) COL1A2 gene IL13 POMC(138-176) STAT6 upregulatedextracellularprotein genesHIF1A gene p-Y641-STAT6 SOCS1 geneSTAT3-upregulatedplasma membraneproteinsNDN VCAM1 IL4R STAT3-upregulatedgenes for plasmamembrane proteinsp-Y-JAK1 IL13 IL4,IL13-upregulatedextracellular genesp-Y705-STAT3 IL13 BATF gene STAT3-upregulatedcytosolic proteinsNDN gene ITGAX gene IGHE CCL22 gene IL23R STAT6 upregulatedplasma membraneprotein genesJAK3 p-Y641-STAT6 BCL6 MCL1 gene IL1A gene STAT3-upregulatedextracellularproteinsJUNB IL13RA2IL4R CCL2 gene ITGAM gene ICAM1 gene IL4 IL13-downregulatedproteinsS1PR1 IL4RIL13RA1 JAK3 IL2RGIL1B gene p-Y-IL4R p-Y-IL2RG IL8 gene LBP gene FN1 gene IL10 IL1B gene STAT1,STAT3,STAT6CCL2 ALOX15 gene IL4 NANOG gene p-Y705-STAT3 dimerp-Y-IL4R p-Y705-STAT3 POU2F1 IL23A p-Y1007-JAK2 IL13:IL13RA:TYK2JAK2 IL4R IL2RG STAT3-upregulatednuclear proteinsIL4R TYK2 IL4 VIM gene BCL2 gene, BCL2L1geneZEB1 ITGB2 gene FN1(32-2386) SOCS3 MMP2 gene p-Y705-STAT3 LIF p-Y641-STAT6 TYK2 IL13RA1 LAMA5 ICAM1 BCL2 gene IL12A gene SOCS3 gene IL13:IL13RA:TYK2:IL4R:JAK2CEBPD TIMP1 p-Y-IL2RG HSPA8 gene, ALOX15geneJAK2 MMP3(100-477) IGHE gene JAK1 SOCS1 IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:p-Y705-STAT3,p-Y641-STAT6ITGB2 CD36 geneJAK2p-Y-IL4R IL4R gene MMP1(84-469) IL4R JAK3 IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1IL13RA1 JAK3 inhibitorsp-Y-TYK2 MMP9(107-707) ADPIL13 FGF2(10-155) ITGAM STAT3 IRF4 IL13IL4:IL4R:JAK2:IL13RA:TYK2:SOCS5,(SOCS1)STAT1 SOX2 IL6R gene JAK3 IL13RA1 FCER2(1-321) ALOX5 ANXA1 gene PTGS2 geneIL4:IL4R:JAK2:IL2RG:JAK3:JAK1p-Y641-STAT6 IL4 IL4,IL13-downregulated genes for extracellular proteinsJAK1 IL4R OPRD1 gene TWIST1 SOCS5 HGF(32-494) ATPp-Y705-STAT3 FOS gene IL13RA1ATPSTAT3-upregulatedgenes forextracellularproteinsFCER2 gene TYK2 TWIST1 gene IGHG4 gene STAT1 gene FCER2 gene p-Y641-STAT6 SOCS5 STAT6 TYK2 MMP1 gene p-Y705-STAT3 AKT1 JAK2 p-Y-TYK2 IL10 gene STAT3 STAT6 upregulatedplasma membraneproteinsTNFRSF1B FOXO1 JAK2 ANXA1 TNF(77-233) MYC IL4:IL4R:JAK2:IL13RA1:TYK2MCL1 FOS p-Y705-STAT3,p-Y641-STAT6HSPA8 IL1B HSPA8, ALOX15PIM1 gene JAK2 IL4 STAT6 p-Y641-STAT6 CCND1 BCL2 ALOX5 gene LAMA5 gene POU2F1 gene IL13-boundtyrosine-phosphorylated IL13R type IIIL4R p-Y705-STAT3 dimer,p-Y614-STAT6 dimerJAK2 IL17F p-Y701-STAT1dimer,p-Y705-STAT3dimer,p-Y641-STAT6dimerVIM MUC1 gene IL13 IL12B BCL2L1 IL8 TYK2 FSCN1 STAT3 IL4 STAT3-upregulatedgenes for cytosolicproteinsIL13 NDN gene, TP53 geneRORA gene IGHG1 STAT3,STAT6LIF gene VEGFA gene p-Y705-STAT3 IL13:IL13RA:TYK2:IL4R:JAK2:JAK1RHOU NDN, TP53HMOX1STAT3-upregulatedgenes for nuclearproteinsJAK3 TGFB1 gene IL4R JAK1 FCER2(1-321) p-Y701-STAT1 SOCS1 Bcl-2/Bcl-X(L)IL18(1-193) IL4, IL13FSCN1 gene BCL2L1 gene IL13OPRM1 IL4R IL6R RORC ADPIL13RA1 p-Y701-STAT1dimer,p-Y705-STAT3dimer,p-Y641-STAT6dimerp-Y705-STAT3 GATA3IL1B,Myr82K-Myr83K-IL1A CDKN1A gene IL4 OPRM1 gene SOX2 gene CCL22(25-93) IL13 p-Y-IL13RA1 IL17A gene IL18, ALOX5STAT3 p-Y-JAK1 JAK2 F13A1 gene NOS2 gene IL4FASLG geneIL23A gene LCN2 FGF2 gene MMP2(110-660) JAK2 p-Y701-STAT1,p-Y705-STAT3,p-Y641-STAT6BATF MMP9 gene MAOA geneIL2RG p-Y641-STAT6 SOCS5,(SOCS1)IGHG4 IL13-upregulatedgenes for plasmamembrane proteinsPIK3R1 p-Y-IL2RG STAT1 p-Y-IL13RA1 IL13RA1:TYK2p-Y-TYK2 JAK3:JAK3 inhibitorsIL18 gene, ALOX5geneMMP3 gene LCN2 gene IL6 FOXO3 gene 4089


Description

Interleukin-4 (IL4) is a principal regulatory cytokine during the immune response, crucially important in allergy and asthma (Nelms et al. 1999). When resting T cells are antigen-activated and expand in response to Interleukin-2 (IL2), they can differentiate as Type 1 (Th1) or Type 2 (Th2) T helper cells. The outcome is influenced by IL4. Th2 cells secrete IL4, which both stimulates Th2 in an autocrine fashion and acts as a potent B cell growth factor to promote humoral immunity (Nelms et al. 1999).

Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003).

IL4 and IL13 induce “alternative activation� of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002)

There are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).

The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).

Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).

Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).

IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013).

IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).

Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013).

A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-Rodríguez 2013).

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  65. Hamilton KE, Simmons JG, Ding S, Van Landeghem L, Lund PK.; ''Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells.''; PubMed Europe PMC Scholia
  66. Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, Gritsko T, Turkson J, Kay H, Semenza GL, Cheng JQ, Jove R, Yu H.; ''Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways.''; PubMed Europe PMC Scholia
  67. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL.; ''An interleukin-4-induced transcription factor: IL-4 Stat.''; PubMed Europe PMC Scholia
  68. Hutt JA, O'Rourke JP, DeWille J.; ''Signal transducer and activator of transcription 3 activates CCAAT enhancer-binding protein delta gene transcription in G0 growth-arrested mouse mammary epithelial cells and in involuting mouse mammary gland.''; PubMed Europe PMC Scholia
  69. Mikita T, Campbell D, Wu P, Williamson K, Schindler U.; ''Requirements for interleukin-4-induced gene expression and functional characterization of Stat6.''; PubMed Europe PMC Scholia
  70. Przanowski P, Dabrowski M, Ellert-Miklaszewska A, Kloss M, Mieczkowski J, Kaza B, Ronowicz A, Hu F, Piotrowski A, Kettenmann H, Komorowski J, Kaminska B.; ''The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia.''; PubMed Europe PMC Scholia
  71. Xu MJ, Feng D, Wu H, Wang H, Chan Y, Kolls J, Borregaard N, Porse B, Berger T, Mak TW, Cowland JB, Kong X, Gao B.; ''Liver is the major source of elevated serum lipocalin-2 levels after bacterial infection or partial hepatectomy: a critical role for IL-6/STAT3.''; PubMed Europe PMC Scholia
  72. Coffer P, Lutticken C, van Puijenbroek A, Klop-de Jonge M, Horn F, Kruijer W.; ''Transcriptional regulation of the junB promoter: analysis of STAT-mediated signal transduction.''; PubMed Europe PMC Scholia
  73. Mikita T, Daniel C, Wu P, Schindler U.; ''Mutational analysis of the STAT6 SH2 domain.''; PubMed Europe PMC Scholia
  74. Chen XS, Zhang Y, Wang JS, Li XY, Cheng XK, Zhang Y, Wu NH, Shen YF.; ''Diverse effects of Stat1 on the regulation of hsp90alpha gene under heat shock.''; PubMed Europe PMC Scholia
  75. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS, Jove R.; ''Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells.''; PubMed Europe PMC Scholia
  76. Davey GM, Heath WR, Starr R.; ''SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation.''; PubMed Europe PMC Scholia
  77. Niu G, Briggs J, Deng J, Ma Y, Lee H, Kortylewski M, Kujawski M, Kay H, Cress WD, Jove R, Yu H.; ''Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells.''; PubMed Europe PMC Scholia
  78. Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C, Sun J, Whipple DA, Changelian PS.; ''Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.''; PubMed Europe PMC Scholia
  79. Schiavone D, Dewilde S, Vallania F, Turkson J, Di Cunto F, Poli V.; ''The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathways.''; PubMed Europe PMC Scholia
  80. Haviland R, Eschrich S, Bloom G, Ma Y, Minton S, Jove R, Cress WD.; ''Necdin, a negative growth regulator, is a novel STAT3 target gene down-regulated in human cancer.''; PubMed Europe PMC Scholia
  81. Harrison DA.; ''The Jak/STAT pathway.''; PubMed Europe PMC Scholia
  82. Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R.; ''Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis.''; PubMed Europe PMC Scholia
  83. Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A.; ''Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1.''; PubMed Europe PMC Scholia
  84. Chi F, Chen L, Wang C, Li L, Sun X, Xu Y, Ma T, Liu K, Ma X, Shu X.; ''JAK3 inhibitors based on thieno[3,2-d]pyrimidine scaffold: design, synthesis and bioactivity evaluation for the treatment of B-cell lymphoma.''; PubMed Europe PMC Scholia
  85. Wu Y, Diab I, Zhang X, Izmailova ES, Zehner ZE.; ''Stat3 enhances vimentin gene expression by binding to the antisilencer element and interacting with the repressor protein, ZBP-89.''; PubMed Europe PMC Scholia
  86. Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih JY, Hung MC.; ''Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway.''; PubMed Europe PMC Scholia
  87. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S.; ''Essential role of Stat6 in IL-4 signalling.''; PubMed Europe PMC Scholia
  88. Bhattacharya S, Ray RM, Johnson LR.; ''STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells.''; PubMed Europe PMC Scholia
  89. Ichinose A, Hendrickson LE, Fujikawa K, Davie EW.; ''Amino acid sequence of the a subunit of human factor XIII.''; PubMed Europe PMC Scholia
  90. Huang YH, Wu MP, Pan SC, Su WC, Chen YW, Wu LW.; ''STAT1 activation by venous malformations mutant Tie2-R849W antagonizes VEGF-A-mediated angiogenic response partly via reduced bFGF production.''; PubMed Europe PMC Scholia
  91. Adamson A, Ghoreschi K, Rittler M, Chen Q, Sun HW, Vahedi G, Kanno Y, Stetler-Stevenson WG, O'Shea JJ, Laurence A.; ''Tissue inhibitor of metalloproteinase 1 is preferentially expressed in Th1 and Th17 T-helper cell subsets and is a direct STAT target gene.''; PubMed Europe PMC Scholia
  92. Roy B, Bhattacharjee A, Xu B, Ford D, Maizel AL, Cathcart MK.; ''IL-13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats.''; PubMed Europe PMC Scholia
  93. Schindler U, Wu P, Rothe M, Brasseur M, McKnight SL.; ''Components of a Stat recognition code: evidence for two layers of molecular selectivity.''; PubMed Europe PMC Scholia
  94. Foshay KM, Gallicano GI.; ''Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate.''; PubMed Europe PMC Scholia
  95. Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, Briggs J, Karras J, Cress WD, Pardoll D, Jove R, Chen J, Yu H.; ''Role of Stat3 in regulating p53 expression and function.''; PubMed Europe PMC Scholia
  96. Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T.; ''STAT3 is required for the gp130-mediated full activation of the c-myc gene.''; PubMed Europe PMC Scholia
  97. Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K, Yoshida K.; ''Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells.''; PubMed Europe PMC Scholia
  98. Hebenstreit D, Wirnsberger G, Horejs-Hoeck J, Duschl A.; ''Signaling mechanisms, interaction partners, and target genes of STAT6.''; PubMed Europe PMC Scholia
  99. Matsukura S, Stellato C, Plitt JR, Bickel C, Miura K, Georas SN, Casolaro V, Schleimer RP.; ''Activation of eotaxin gene transcription by NF-kappa B and STAT6 in human airway epithelial cells.''; PubMed Europe PMC Scholia
  100. Oh HM, Yu CR, Golestaneh N, Amadi-Obi A, Lee YS, Eseonu A, Mahdi RM, Egwuagu CE.; ''STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors.''; PubMed Europe PMC Scholia
  101. Song Y, Qian L, Song S, Chen L, Zhang Y, Yuan G, Zhang H, Xia Q, Hu M, Yu M, Shi M, Jiang Z, Guo N.; ''Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115055view16:59, 25 January 2021ReactomeTeamReactome version 75
113499view11:57, 2 November 2020ReactomeTeamReactome version 74
112699view16:09, 9 October 2020ReactomeTeamReactome version 73
101615view11:48, 1 November 2018ReactomeTeamreactome version 66
101151view21:34, 31 October 2018ReactomeTeamreactome version 65
100679view20:07, 31 October 2018ReactomeTeamreactome version 64
100229view16:52, 31 October 2018ReactomeTeamreactome version 63
99780view15:18, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93379view11:22, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
4xPalmC-CD36ProteinP16671 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT1 gene ProteinENSG00000142208 (Ensembl)
ALOX15 ProteinP16050 (Uniprot-TrEMBL)
ALOX15 gene ProteinENSG00000161905 (Ensembl)
ALOX5 ProteinP09917 (Uniprot-TrEMBL)
ALOX5 gene ProteinENSG00000012779 (Ensembl)
ANXA1 ProteinP04083 (Uniprot-TrEMBL)
ANXA1 gene ProteinENSG00000135046 (Ensembl)
ATPMetaboliteCHEBI:30616 (ChEBI)
BATF ProteinQ16520 (Uniprot-TrEMBL)
BATF gene ProteinENSG00000156127 (Ensembl)
BCL2 ProteinP10415 (Uniprot-TrEMBL)
BCL2 gene ProteinENSG00000171791 (Ensembl)
BCL2 gene, BCL2L1 geneComplexR-HSA-6790035 (Reactome)
BCL2L1 ProteinQ07817 (Uniprot-TrEMBL)
BCL2L1 gene ProteinENSG00000171552 (Ensembl)
BCL6 ProteinP41182 (Uniprot-TrEMBL)
BCL6 gene ProteinENSG00000113916 (Ensembl)
BIRC5 ProteinO15392 (Uniprot-TrEMBL)
BIRC5 gene ProteinENSG00000089685 (Ensembl)
Bcl-2/Bcl-X(L)ComplexR-HSA-879209 (Reactome)
CCL11 ProteinP51671 (Uniprot-TrEMBL)
CCL11 gene ProteinENSG00000172156 (Ensembl)
CCL2 ProteinP13500 (Uniprot-TrEMBL)
CCL2 gene ProteinENSG00000108691 (Ensembl)
CCL22 gene ProteinENSG00000102962 (Ensembl)
CCL22(25-93) ProteinO00626 (Uniprot-TrEMBL)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND1 gene ProteinENSG00000110092 (Ensembl)
CD36 geneGeneProductENSG00000135218 (Ensembl)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CEBPD ProteinP49716 (Uniprot-TrEMBL)
CEBPD gene ProteinENSG00000221869 (Ensembl)
COL1A2 ProteinP08123 (Uniprot-TrEMBL)
COL1A2 gene ProteinENSG00000164692 (Ensembl)
F13A1 gene ProteinENSG00000124491 (Ensembl)
FASLG geneGeneProductENSG00000117560 (Ensembl)
FASLG(1-281)ProteinP48023 (Uniprot-TrEMBL)
FCER2 gene ProteinENSG00000104921 (Ensembl)
FCER2(1-321) ProteinP06734 (Uniprot-TrEMBL)
FGF2 gene ProteinENSG00000138685 (Ensembl)
FGF2(10-155) ProteinP09038 (Uniprot-TrEMBL)
FN1 gene ProteinENSG00000115414 (Ensembl)
FN1(32-2386) ProteinP02751 (Uniprot-TrEMBL)
FOS ProteinP01100 (Uniprot-TrEMBL)
FOS gene ProteinENSG00000170345 (Ensembl)
FOXO1 ProteinQ12778 (Uniprot-TrEMBL)
FOXO1 gene ProteinENSG00000150907 (Ensembl)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO3 gene ProteinENSG00000118689 (Ensembl)
FSCN1 ProteinQ16658 (Uniprot-TrEMBL)
FSCN1 gene ProteinENSG00000075618 (Ensembl)
GATA3 geneGeneProductENSG00000107485 (Ensembl)
GATA3ProteinP23771 (Uniprot-TrEMBL)
HGF gene ProteinENSG00000019991 (Ensembl)
HGF(32-494) ProteinP14210 (Uniprot-TrEMBL)
HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HIF1A gene ProteinENSG00000100644 (Ensembl)
HMOX1 geneGeneProductENSG00000100292 (Ensembl)
HMOX1ProteinP09601 (Uniprot-TrEMBL)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AA1 gene ProteinENSG00000080824 (Ensembl)
HSP90B1ProteinP14625 (Uniprot-TrEMBL)
HSPA8 ProteinP11142 (Uniprot-TrEMBL)
HSPA8 gene ProteinENSG00000109971 (Ensembl)
HSPA8 gene, ALOX15 geneComplexR-HSA-6797266 (Reactome)
HSPA8, ALOX15ComplexR-HSA-6797275 (Reactome)
ICAM1 ProteinP05362 (Uniprot-TrEMBL)
ICAM1 gene ProteinENSG00000090339 (Ensembl)
IGHE ProteinP01854 (Uniprot-TrEMBL)
IGHE gene ProteinENSG00000211891 (Ensembl)
IGHG1 ProteinP01857 (Uniprot-TrEMBL)
IGHG1 gene ProteinENSG00000211896 (Ensembl)
IGHG4 ProteinP01861 (Uniprot-TrEMBL)
IGHG4 gene ProteinENSG00000211892 (Ensembl)
IL10 ProteinP22301 (Uniprot-TrEMBL)
IL10 gene ProteinENSG00000136634 (Ensembl)
IL12A ProteinP29459 (Uniprot-TrEMBL)
IL12A gene ProteinENSG00000168811 (Ensembl)
IL12B ProteinP29460 (Uniprot-TrEMBL)
IL12B gene ProteinENSG00000113302 (Ensembl)
IL13 ProteinP35225 (Uniprot-TrEMBL)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6ComplexR-HSA-6788579 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with phosphorylated STAT1,STAT3,STAT6ComplexR-HSA-6788621 (Reactome)
IL13-bound tyrosine-phosphorylated IL13R type IIComplexR-HSA-6786783 (Reactome)
IL13-downregulated

genes for extracellular

proteins
ComplexR-HSA-6789360 (Reactome)
IL13-downregulated proteinsComplexR-HSA-6789357 (Reactome)
IL13-upregulated

genes for plasma

membrane proteins
ComplexR-HSA-6789363 (Reactome)
IL13-upregulated proteinsComplexR-HSA-6789331 (Reactome)
IL13:IL13RA2ComplexR-HSA-449798 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2:JAK1ComplexR-HSA-6786093 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2ComplexR-HSA-6786083 (Reactome)
IL13:IL13RA:TYK2ComplexR-HSA-6786060 (Reactome)
IL13ProteinP35225 (Uniprot-TrEMBL)
IL13RA1 ProteinP78552 (Uniprot-TrEMBL)
IL13RA1:TYK2ComplexR-HSA-6785829 (Reactome)
IL13RA1ProteinP78552 (Uniprot-TrEMBL)
IL13RA2 ProteinQ14627 (Uniprot-TrEMBL)
IL13RA2ProteinQ14627 (Uniprot-TrEMBL)
IL17A ProteinQ16552 (Uniprot-TrEMBL)
IL17A gene ProteinENSG00000112115 (Ensembl)
IL17F ProteinQ96PD4 (Uniprot-TrEMBL)
IL17F gene ProteinENSG00000112116 (Ensembl)
IL18 gene ProteinENSG00000150782 (Ensembl)
IL18 gene, ALOX5 geneComplexR-HSA-6797290 (Reactome)
IL18(1-193) ProteinQ14116 (Uniprot-TrEMBL)
IL18, ALOX5ComplexR-HSA-6797291 (Reactome)
IL1A gene ProteinENSG00000115008 (Ensembl)
IL1B ProteinP01584 (Uniprot-TrEMBL)
IL1B gene ProteinENSG00000125538 (Ensembl)
IL1B,Myr82K-Myr83K-IL1A R-HSA-445744 (Reactome)
IL23A ProteinQ9NPF7 (Uniprot-TrEMBL)
IL23A gene ProteinENST00000619177 (Ensembl)
IL23R ProteinQ5VWK5 (Uniprot-TrEMBL)
IL23R gene ProteinENSG00000162594 (Ensembl)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
IL2RG:JAK3ComplexR-HSA-451911 (Reactome)
IL2RGProteinP31785 (Uniprot-TrEMBL)
IL4 ProteinP05112 (Uniprot-TrEMBL)
IL4, IL13ComplexR-HSA-6797283 (Reactome)
IL4,IL13-downregulated extracellular proteinsComplexR-HSA-6789485 (Reactome)
IL4,IL13-downregulated genes for extracellular proteinsComplexR-HSA-6789520 (Reactome)
IL4,IL13-upregulated

extracellular

proteins
ComplexR-HSA-6789504 (Reactome)
IL4,IL13-upregulated extracellular genesComplexR-HSA-6789505 (Reactome)
IL4:IL4R:JAK2:IL13RA1:TYK2ComplexR-HSA-6786102 (Reactome)
IL4:IL4R:JAK2:IL13RA:TYK2:SOCS5,(SOCS1)ComplexR-HSA-6788313 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3:JAK1ComplexR-HSA-6786090 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3ComplexR-HSA-6786078 (Reactome)
IL4:IL4R:JAK2ComplexR-HSA-6786075 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6ComplexR-HSA-6786077 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:p-Y705-STAT3,p-Y641-STAT6ComplexR-HSA-6786088 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1ComplexR-HSA-6786061 (Reactome)
IL4ProteinP05112 (Uniprot-TrEMBL)
IL4R ProteinP24394 (Uniprot-TrEMBL)
IL4R gene ProteinENSG00000077238 (Ensembl)
IL4R:JAK2ComplexR-HSA-6785800 (Reactome)
IL4RProteinP24394 (Uniprot-TrEMBL)
IL6 ProteinP05231 (Uniprot-TrEMBL)
IL6 gene ProteinENSG00000136244 (Ensembl)
IL6R ProteinP08887 (Uniprot-TrEMBL)
IL6R gene ProteinENSG00000160712 (Ensembl)
IL8 ProteinP10145 (Uniprot-TrEMBL)
IL8 gene ProteinENSG00000169429 (Ensembl)
IRF4 ProteinQ15306 (Uniprot-TrEMBL)
IRF4 gene ProteinENSG00000137265 (Ensembl)
ITGAM ProteinP11215 (Uniprot-TrEMBL)
ITGAM gene ProteinENSG00000169896 (Ensembl)
ITGAX ProteinP20702 (Uniprot-TrEMBL)
ITGAX gene ProteinENSG00000140678 (Ensembl)
ITGB1 Gene ProteinENSG00000150093 (Ensembl)
ITGB1 ProteinP05556 (Uniprot-TrEMBL)
ITGB2 gene ProteinENSG00000160255 (Ensembl)
ITGB2 ProteinP05107 (Uniprot-TrEMBL)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK1ProteinP23458 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
JAK3 inhibitorsComplexR-ALL-9678772 (Reactome)
JAK3:JAK3 inhibitorsComplexR-HSA-9678869 (Reactome)
JAK3ProteinP52333 (Uniprot-TrEMBL)
JUNB ProteinP17275 (Uniprot-TrEMBL)
JUNB gene ProteinENSG00000171223 (Ensembl)
LAMA5 ProteinO15230 (Uniprot-TrEMBL)
LAMA5 gene ProteinENSG00000130702 (Ensembl)
LBP ProteinP18428 (Uniprot-TrEMBL)
LBP gene ProteinENSG00000129988 (Ensembl)
LCN2 ProteinP80188 (Uniprot-TrEMBL)
LCN2 gene ProteinENSG00000148346 (Ensembl)
LIF ProteinP15018 (Uniprot-TrEMBL)
LIF gene ProteinENSG00000128342 (Ensembl)
MAOA geneGeneProductENSG00000189221 (Ensembl)
MAOAProteinP21397 (Uniprot-TrEMBL)
MCL1 ProteinQ07820 (Uniprot-TrEMBL)
MCL1 gene ProteinENSG00000143384 (Ensembl)
MMP1 gene ProteinENSG00000196611 (Ensembl)
MMP1(84-469) ProteinP03956 (Uniprot-TrEMBL)
MMP2 gene ProteinENSG00000087245 (Ensembl)
MMP2(110-660) ProteinP08253 (Uniprot-TrEMBL)
MMP3 gene ProteinENSG00000149968 (Ensembl)
MMP3(100-477) ProteinP08254 (Uniprot-TrEMBL)
MMP9 gene ProteinENSG00000100985 (Ensembl)
MMP9(107-707) ProteinP14780 (Uniprot-TrEMBL)
MUC1 gene ProteinENSG00000185499 (Ensembl)
MUC1(24-1255) ProteinP15941 (Uniprot-TrEMBL)
MYC ProteinP01106 (Uniprot-TrEMBL)
MYC gene ProteinENSG00000136997 (Ensembl)
Myr82K-Myr83K-IL1A ProteinP01583 (Uniprot-TrEMBL)
NANOG ProteinQ9H9S0 (Uniprot-TrEMBL)
NANOG gene ProteinENSG00000111704 (Ensembl)
NDN ProteinQ99608 (Uniprot-TrEMBL)
NDN gene ProteinENSG00000182636 (Ensembl)
NDN gene, TP53 geneComplexR-HSA-6797247 (Reactome)
NDN, TP53ComplexR-HSA-6789965 (Reactome)
NOS2 ProteinP35228 (Uniprot-TrEMBL)
NOS2 gene ProteinENSG00000007171 (Ensembl)
OPRD1 ProteinP41143 (Uniprot-TrEMBL)
OPRD1 gene ProteinENSG00000116329 (Ensembl)
OPRM1 ProteinP35372 (Uniprot-TrEMBL)
OPRM1 gene ProteinENSG00000112038 (Ensembl)
OSM ProteinP13725 (Uniprot-TrEMBL)
OSM gene ProteinENSG00000099985 (Ensembl)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1 gene ProteinENSG00000145675 (Ensembl)
PIM1 ProteinP11309 (Uniprot-TrEMBL)
PIM1 gene ProteinENSG00000137193 (Ensembl)
POMC gene ProteinENSG00000115138 (Ensembl)
POMC(138-176) ProteinP01189 (Uniprot-TrEMBL)
POU2F1 ProteinP14859 (Uniprot-TrEMBL)
POU2F1 gene ProteinENSG00000143190 (Ensembl)
PTGS2 geneGeneProductENSG00000073756 (Ensembl)
PTGS2ProteinP35354 (Uniprot-TrEMBL)
RHOU ProteinQ7L0Q8 (Uniprot-TrEMBL)
RHOU gene ProteinENSG00000116574 (Ensembl)
RORA ProteinP35398 (Uniprot-TrEMBL)
RORA gene ProteinENSG00000069667 (Ensembl)
RORC ProteinP51449 (Uniprot-TrEMBL)
RORC gene ProteinENSG00000143365 (Ensembl)
S1PR1 ProteinP21453 (Uniprot-TrEMBL)
S1PR1 gene ProteinENSG00000170989 (Ensembl)
SAA1 gene ProteinENSG00000173432 (Ensembl)
SAA1(19-122) ProteinP0DJI8 (Uniprot-TrEMBL)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS1 geneGeneProductENSG00000185338 (Ensembl)
SOCS1ProteinO15524 (Uniprot-TrEMBL)
SOCS3 ProteinO14543 (Uniprot-TrEMBL)
SOCS3 gene ProteinENSG00000184557 (Ensembl)
SOCS5 ProteinO75159 (Uniprot-TrEMBL)
SOCS5,(SOCS1)ComplexR-HSA-6788320 (Reactome)
SOX2 ProteinP48431 (Uniprot-TrEMBL)
SOX2 gene ProteinENSG00000181449 (Ensembl)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1 gene ProteinENSG00000115415 (Ensembl)
STAT1,STAT3,STAT6ComplexR-HSA-6788573 (Reactome)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT3,STAT6ComplexR-HSA-6786055 (Reactome)
STAT3-upregulated cytosolic proteinsComplexR-HSA-6790032 (Reactome)
STAT3-upregulated

extracellular

proteins
ComplexR-HSA-6790034 (Reactome)
STAT3-upregulated

genes for extracellular

proteins
ComplexR-HSA-6790043 (Reactome)
STAT3-upregulated

genes for cytosolic

proteins
ComplexR-HSA-6790033 (Reactome)
STAT3-upregulated

genes for nuclear

proteins
ComplexR-HSA-6790023 (Reactome)
STAT3-upregulated

genes for plasma

membrane proteins
ComplexR-HSA-6790031 (Reactome)
STAT3-upregulated nuclear proteinsComplexR-HSA-6790042 (Reactome)
STAT3-upregulated

plasma membrane

proteins
ComplexR-HSA-6789797 (Reactome)
STAT6 ProteinP42226 (Uniprot-TrEMBL)
STAT6 upregulated

extracellular

protein genes
ComplexR-HSA-6793980 (Reactome)
STAT6 upregulated

extracellular

proteins
ComplexR-HSA-6793985 (Reactome)
STAT6 upregulated

plasma membrane

protein genes
ComplexR-HSA-6793996 (Reactome)
STAT6 upregulated

plasma membrane

proteins
ComplexR-HSA-6793974 (Reactome)
TGFB1 gene ProteinENSG00000105329 (Ensembl)
TGFB1(30-278) ProteinP01137 (Uniprot-TrEMBL)
TIMP1 ProteinP01033 (Uniprot-TrEMBL)
TIMP1 gene ProteinENSG00000102265 (Ensembl)
TNF gene ProteinENSG00000232810 (Ensembl)
TNF(77-233) ProteinP01375 (Uniprot-TrEMBL)
TNFRSF1B ProteinP20333 (Uniprot-TrEMBL)
TNFRSF1B gene ProteinENSG00000028137 (Ensembl)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 gene ProteinENSG00000141510 (Ensembl)
TWIST1 ProteinQ15672 (Uniprot-TrEMBL)
TWIST1 gene ProteinENSG00000122691 (Ensembl)
TYK2 ProteinP29597 (Uniprot-TrEMBL)
TYK2ProteinP29597 (Uniprot-TrEMBL)
VCAM1 ProteinP19320 (Uniprot-TrEMBL)
VCAM1 gene ProteinENSG00000162692 (Ensembl)
VEGFA ProteinP15692 (Uniprot-TrEMBL)
VEGFA gene ProteinENSG00000112715 (Ensembl)
VIM ProteinP08670 (Uniprot-TrEMBL)
VIM gene ProteinENSG00000026025 (Ensembl)
ZEB1 ProteinP37275 (Uniprot-TrEMBL)
ZEB1 gene ProteinENSG00000148516 (Ensembl)
baricitinib
factor XIII A chain ProteinP00488 (Uniprot-TrEMBL)
p-Y-IL13RA1 ProteinP78552 (Uniprot-TrEMBL)
p-Y-IL2RG ProteinP31785 (Uniprot-TrEMBL)
p-Y-IL4R ProteinP24394 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y641-STAT6 ProteinP42226 (Uniprot-TrEMBL)
p-Y641-STAT6 dimerComplexR-HSA-6786281 (Reactome)
p-Y701-STAT1

dimer,p-Y705-STAT3 dimer,p-Y641-STAT6

dimer
ComplexR-HSA-6788618 (Reactome)
p-Y701-STAT1

dimer,p-Y705-STAT3 dimer,p-Y641-STAT6

dimer
ComplexR-HSA-6788619 (Reactome)
p-Y701-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-Y701-STAT1,p-Y705-STAT3,p-Y641-STAT6ComplexR-HSA-6788625 (Reactome)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3 dimer, p-Y614-STAT6 dimerComplexR-HSA-6788580 (Reactome)
p-Y705-STAT3 dimer, p-Y641-STAT6 dimerComplexR-HSA-6788575 (Reactome)
p-Y705-STAT3 dimerComplexR-HSA-1112525 (Reactome)
p-Y705-STAT3,p-Y641-STAT6ComplexR-HSA-6786065 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xPalmC-CD36ArrowR-HSA-6797267 (Reactome)
ADPArrowR-HSA-6786050 (Reactome)
ADPArrowR-HSA-6786095 (Reactome)
ADPArrowR-HSA-6786096 (Reactome)
ADPArrowR-HSA-6788582 (Reactome)
ATPR-HSA-6786050 (Reactome)
ATPR-HSA-6786095 (Reactome)
ATPR-HSA-6786096 (Reactome)
ATPR-HSA-6788582 (Reactome)
BCL2 gene, BCL2L1 geneR-HSA-6790025 (Reactome)
Bcl-2/Bcl-X(L)ArrowR-HSA-6790025 (Reactome)
CD36 geneR-HSA-6797267 (Reactome)
FASLG geneR-HSA-6797245 (Reactome)
FASLG(1-281)ArrowR-HSA-6797245 (Reactome)
GATA3 geneR-HSA-6793975 (Reactome)
GATA3ArrowR-HSA-6793975 (Reactome)
HMOX1 geneR-HSA-6797268 (Reactome)
HMOX1ArrowR-HSA-6797268 (Reactome)
HSP90B1ArrowR-HSA-6790038 (Reactome)
HSPA8 gene, ALOX15 geneR-HSA-6797269 (Reactome)
HSPA8, ALOX15ArrowR-HSA-6797269 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6ArrowR-HSA-6788571 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6R-HSA-6788582 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with STAT1,STAT3,STAT6mim-catalysisR-HSA-6788582 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with phosphorylated STAT1,STAT3,STAT6ArrowR-HSA-6788582 (Reactome)
IL13-bound tyrosine-phosphorylated IL13 receptor type II with phosphorylated STAT1,STAT3,STAT6R-HSA-6788628 (Reactome)
IL13-bound tyrosine-phosphorylated IL13R type IIArrowR-HSA-6786050 (Reactome)
IL13-bound tyrosine-phosphorylated IL13R type IIArrowR-HSA-6788628 (Reactome)
IL13-bound tyrosine-phosphorylated IL13R type IIR-HSA-6788571 (Reactome)
IL13-downregulated

genes for extracellular

proteins
R-HSA-6789325 (Reactome)
IL13-downregulated proteinsArrowR-HSA-6789325 (Reactome)
IL13-upregulated

genes for plasma

membrane proteins
R-HSA-6788346 (Reactome)
IL13-upregulated proteinsArrowR-HSA-6788346 (Reactome)
IL13:IL13RA2ArrowR-HSA-449818 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2:JAK1ArrowR-HSA-6786110 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2:JAK1R-HSA-6786050 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2ArrowR-HSA-6786114 (Reactome)
IL13:IL13RA:TYK2:IL4R:JAK2R-HSA-6786110 (Reactome)
IL13:IL13RA:TYK2ArrowR-HSA-6786118 (Reactome)
IL13:IL13RA:TYK2R-HSA-6786114 (Reactome)
IL13ArrowR-HSA-6788346 (Reactome)
IL13R-HSA-449818 (Reactome)
IL13R-HSA-6786118 (Reactome)
IL13RA1:TYK2ArrowR-HSA-6785762 (Reactome)
IL13RA1:TYK2R-HSA-6786070 (Reactome)
IL13RA1:TYK2R-HSA-6786118 (Reactome)
IL13RA1R-HSA-6785762 (Reactome)
IL13RA2R-HSA-449818 (Reactome)
IL13TBarR-HSA-6789325 (Reactome)
IL18 gene, ALOX5 geneR-HSA-6797293 (Reactome)
IL18, ALOX5ArrowR-HSA-6797293 (Reactome)
IL2RG:JAK3ArrowR-HSA-451895 (Reactome)
IL2RG:JAK3R-HSA-6786092 (Reactome)
IL2RGR-HSA-451895 (Reactome)
IL4, IL13ArrowR-HSA-6785895 (Reactome)
IL4, IL13ArrowR-HSA-6797267 (Reactome)
IL4, IL13ArrowR-HSA-6797268 (Reactome)
IL4, IL13ArrowR-HSA-6797269 (Reactome)
IL4, IL13ArrowR-HSA-6797271 (Reactome)
IL4, IL13TBarR-HSA-6789524 (Reactome)
IL4, IL13TBarR-HSA-6797293 (Reactome)
IL4,IL13-downregulated extracellular proteinsArrowR-HSA-6789524 (Reactome)
IL4,IL13-downregulated genes for extracellular proteinsR-HSA-6789524 (Reactome)
IL4,IL13-upregulated

extracellular

proteins
ArrowR-HSA-6785895 (Reactome)
IL4,IL13-upregulated extracellular genesR-HSA-6785895 (Reactome)
IL4:IL4R:JAK2:IL13RA1:TYK2ArrowR-HSA-6786070 (Reactome)
IL4:IL4R:JAK2:IL13RA1:TYK2R-HSA-6785821 (Reactome)
IL4:IL4R:JAK2:IL13RA:TYK2:SOCS5,(SOCS1)ArrowR-HSA-6785821 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3:JAK1ArrowR-HSA-6786058 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3:JAK1R-HSA-6786096 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3:JAK1mim-catalysisR-HSA-6786096 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3ArrowR-HSA-6786092 (Reactome)
IL4:IL4R:JAK2:IL2RG:JAK3R-HSA-6786058 (Reactome)
IL4:IL4R:JAK2ArrowR-HSA-6786101 (Reactome)
IL4:IL4R:JAK2R-HSA-6786070 (Reactome)
IL4:IL4R:JAK2R-HSA-6786092 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6ArrowR-HSA-6786124 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6R-HSA-6786095 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:STAT3,STAT6mim-catalysisR-HSA-6786095 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:p-Y705-STAT3,p-Y641-STAT6ArrowR-HSA-6786095 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1:p-Y705-STAT3,p-Y641-STAT6R-HSA-6786072 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1ArrowR-HSA-6786072 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1ArrowR-HSA-6786096 (Reactome)
IL4:p-Y-IL4R:JAK2:p-Y-IL2RG:JAK3:p-Y-JAK1R-HSA-6786124 (Reactome)
IL4R-HSA-6786101 (Reactome)
IL4R:JAK2ArrowR-HSA-6785898 (Reactome)
IL4R:JAK2R-HSA-6786101 (Reactome)
IL4R:JAK2R-HSA-6786114 (Reactome)
IL4RR-HSA-6785898 (Reactome)
JAK1R-HSA-6786058 (Reactome)
JAK1R-HSA-6786110 (Reactome)
JAK2R-HSA-6785898 (Reactome)
JAK3 inhibitorsR-HSA-9679028 (Reactome)
JAK3:JAK3 inhibitorsArrowR-HSA-9679028 (Reactome)
JAK3:JAK3 inhibitorsTBarR-HSA-451895 (Reactome)
JAK3R-HSA-451895 (Reactome)
JAK3R-HSA-9679028 (Reactome)
MAOA geneR-HSA-6797271 (Reactome)
MAOAArrowR-HSA-6797271 (Reactome)
NDN gene, TP53 geneR-HSA-6789960 (Reactome)
NDN, TP53ArrowR-HSA-6789960 (Reactome)
PTGS2 geneR-HSA-6790029 (Reactome)
PTGS2ArrowR-HSA-6790029 (Reactome)
R-HSA-449818 (Reactome) Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP) is a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997); overexpression reduces STAT6 signaling (Kawakami et al. 2001). Its function may be to prevent IL13 signaling via the functional IL4R:IL13RA1 cell surface receptor. IL13BP is overexpressed in some human cancers and enhances cell invasion (Joshi & Puri 2012).
R-HSA-451895 (Reactome) Cytokine receptor common gamma subunit (IL2RG, IL-2 receptor gamma chain, Gc) associates with Tyrosine-protein kinase JAK3 (JAK3). The carboxyl-terminal region of IL2RG is important for this association (Miyazaki et al. 1994, Zhu et al. 1998, Russel et al. 2004, Chen et al.1997, Nelson et al.1994) as well as the FERM domain in JAK3 (Zhou et al. 2001).
R-HSA-6785762 (Reactome) Interleukin-13 receptor subunit alpha-1 (IL13RA1) constitutively associates with Non-receptor tyrosine-protein kinase 2 (TYK2) (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).
R-HSA-6785821 (Reactome) SOCS5 can bind the type I IL4R, reducing its association with JAK1, which results in the inhibition of IL4-mediated STAT6 activation (Seki et al. 2002). Similarly SOCS1 serves as a regulator of IL-4 signaling, diminishing the magnitude and duration of STAT6 activation (Dickensheets et al. 2007).
R-HSA-6785860 (Reactome) Phosphorylated Signal transducer and activator of transcription 6 (STAT6) dimers translocate to the nucleus and activate the transcription of several genes. In experimental models, targeted gene disruption of STAT6 inhibited airway hyper-responsiveness, airway inflammation, and fibrosis (Blease et al. 2002). STAT6 promotes transcription of the cytoplasmic protein Suppressor of cytokine signaling 1 (SOCS1) (Hebenstreit et al. 2003).
R-HSA-6785895 (Reactome) In human peripheral blood monocytes IL4 and IL13 significantly upregulate the levels of several extracellular proteins involved in inflammatory resolution including fibronectin (FN1), coagulation factor XIII (FXIII), annexin 1 (ANXA1), collagen type 1 alpha 2 (COL1A2), laminin alpha-5 (LAMA5) and C-C motif chemokine 22 (CCL22) (Chaitidis et al. 2005, Jinnin et al. 2004, Yakubenko et al. 2011).
R-HSA-6785898 (Reactome) The interleukin-4 receptor (IL4R) constitutively binds Janus kinase 2 (JAK2) (Roy et al. 2002).
R-HSA-6786050 (Reactome) Interleukin-4 receptor alpha subunit (IL4R) and Interleukin-13 receptor subunit alpha 1 (IL13RA1) are phosphorylated on tyrosines in response to Interleukin-13 (IL13) in human blood monocytes (Roy et al. 2002, Bhattacharjee et al. 2013). The associated Janus-kinase (JAK) family kinases JAK2 and TYK2 are also phosphorylated (Roy & Cathcart 1998, Bhattacharjee et al. 2013). Although JAK1 binds to IL4R in response to IL13, it does not appear to be phosphorylated in response to IL13 (Roy & Cathcart 1998, Bhattacharjee et al. 2013).
R-HSA-6786058 (Reactome) In human blood monocytes, where the type I interleukin-4 (IL4) receptor (IL4R1) is the predominant IL4 receptor type, IL4 leads to tyrosine phosphorylation of Janus kinase 1 (JAK1), rather than constitutively bound JAK2, JAK3 or Non-receptor associated tyrosine kinase 2 (TYK2). JAK1 was found to be essential for IL4-mediated expression of 15-lipoxygenase while JAK2 and TYK2 antisense inhibition had no effect (Bhattacharjee et al. 2013). As JAK1 binds IL4RA in response to IL13 binding (Roy et al. 2002), it is believed that IL4 similarly triggers binding of JAK1 to IL4 receptor complexes. The molecular trigger for JAK1 binding is not clear.
R-HSA-6786070 (Reactome) Interleukin-13 receptor subunit alpha-1 (IL13RA1), with associated Non-receptor tyrosine-protein kinase 2 (TYK2), binds the IL4:IL4R:JAK2 complex to form the ligand-bound Type II IL4 receptor complex (IL4R2). IL4R2 is predominantly expressed on the surface of non-hematopoietic cells. It is also a receptor for Interleukin-13 (IL13) (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996). Crystal structures of the IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008).
R-HSA-6786072 (Reactome) Once phosphorylated, Signal transducer and activator of transcription 3 (STAT3) and STAT6 dissociate from the IL4 receptor/JAK1 complex.
R-HSA-6786092 (Reactome) Interleukin 2 receptor gamma subunit (IL2RG), with constitutively-associated Janus kinase 3 (JAK3), binds the IL4:IL4R:JAK2 complex, interacting with IL4 and IL4R to form the ligand-bound type I IL4 receptor complex, IL4R1 (LaPorte et al. 2008).
R-HSA-6786095 (Reactome) Signal transducer and activator of transcription 3 (STAT3) and STAT6 are phosphorylated by Janus kinase 1 (JAK1) in response to Interleukin-4 (IL4) (Bhattacharjee et al. 2013). STAT3 is phosphorylated on Y705, STAT6 is phosphorylated on Y641, residues critical for their function (Schindler & Darnell 1995, Mikita et al. 1996).
R-HSA-6786096 (Reactome) Interleukin-4 receptor subunit apha (IL4R), Interleukin-2 receptor subunit gamma (IL2RG) and Janus kinase 1 (JAK1), but not Non-receptor associated tyrosine kinase 2 (TYK2), JAK2 or JAK3 are tyrosine phosphorylated in response to IL4 (Bhattacharjee et al. 2013). The order of these phosphorylation events is not clear. Based on studies of other interleukin receptors and their associated JAKs it is likely that JAK1 autophosphorylates and then phosphorylates IL4R and IL2RG.

IL4R contains 5 conserved tyrosine residues, Y497, Y575, Y603, Y631, and Y713, which can all play a role in signaling through this receptor. Structure-function analyses have revealed that Y497 is part of the IL4R motif that is necessary for the recruitment of IRS1 and IRS2 to IL4R and is critical for IL4-dependent cell proliferation (Keegan et al. 1994). STAT6 signaling requires one of tyrosines Y575, Y603, and Y631 (Ryan et al. 1996). Y713 is part of an immunotyrosine-based inhibitory motif (ITIM) shown to be important in the negative regulation of IL4 and IL13 responses (Kashiwada et al. 2001).
R-HSA-6786097 (Reactome) According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other (Shuai et al. 1994, Mikita et al. 1996). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states, and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
R-HSA-6786101 (Reactome) The first step in the formation of both types of IL4 receptor is the binding of Interleukin-4 (IL4) with Interleukin-4 receptor subunit alpha (IL4R) , which has Janus kinase 2 (JAK2) constitutively associated (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999).
R-HSA-6786110 (Reactome) In response to Interleukin-13 ( IL13) binding, Janus kinase 1 (JAK1) binds to Interleukin-4 receptor alpha subunit (IL4R) (Roy et al. 2002). IL4R has 2 JAK binding motifs so it is believed that IL4R can bind JAK2 constitutively and additionally bind JAK1 upon ligand binding. The molecular trigger for JAK1 binding is not clear.
R-HSA-6786114 (Reactome) Interleukin-13 receptor alpha subunit (IL13RA1) binds Interleukin-13 (IL13) with a relatively low affinity, but when paired with Interleukin-4 receptor subunit alpha (IL4R), binds with much higher affinity (Kd = 400 pmol/L) and forms a functional IL13 receptor that is capable of signaling (Miloux et al. 1997). This type II IL13 receptor complex is also the alternative type II receptor for IL4.
R-HSA-6786118 (Reactome) The type II Interleukin-13 (IL13) receptor complex (IL13R2) forms with IL13 binding to Interleukin-13 receptor alpha subunit 1 (IL13RA1), which is constitutively bound to Non-receptor tyrosine kinase 2 (TYK2), followed by recruitment of Interleukin-4 receptor subunit alpha (IL4R), which is associated with Janus kinase 2 (JAK2) (Wang et al. 2009). IL13RA1 binds IL13 with low affinity (Kd = 2-10 nmol/L) (Miloux et al. 1997).
R-HSA-6786124 (Reactome) Signal transducer and activator of transcription 6 (STAT6) binds to tyrosine-phosphorylated Interleukin-4 receptor subunit alpha (IL4R) (Hou et al. 1994, Schindler et al. 1996, Mikita et al. 1998). Binding of STAT3 has also been reported (Rahaman et al. 2005, Bhattacharjee et al. 2013) but is sometimes reported to be dependent on interleukin-13 receptor subunit alpha (IL13RA) rather than IL4R (Umeshita-Suyama et al. 2000). Other reports have suggested that STAT3 is not phosphorylated in response to IL4 (Friedrich et al. 1999). Consistent with the fact that IL4 and IL13 receptors both incorporate IL4R, they also share common signaling pathways. IL4R is believed to be the signaling component of both IL4 and IL13 receptors because treatment with either generates intermediates that are characteristic of IL4 responses, including phosphorylation of IL4R, insulin receptor substrate 2 (IRS2), Janus kinase 1 (JAK1), and Non-receptor tyrosine-protein kinase 2 (TYK2) (Welham et al. 1995). STAT6-deficient mice suggest that IL13 signaling, like IL4 signaling, uses STAT6 (Takeda et al. 1996, Kaplan et al. 1996). STAT1 activation in response to IL4 has been reported (Wang et al. 2004) but also disputed (Bhattacharjee et al. 2013).
R-HSA-6786293 (Reactome) Phosphorylated, dimerized Signal transducer and activator of transcription 6 (STAT6) translocates to the nucleus where it regulates the expression of multiple genes (Mikita et al. 1996, Daines et al. 2003, Hebenstreit et al. 2006, Goenka & Kaplan 2011).
R-HSA-6788346 (Reactome) In monocytes and macrophages Interleukin-13 (IL13) enhances the expression of many members of the integrin family including Integrin alpha M (ITGAM, CD11b), Integrin alpha-X (ITGAX, CD11c), Integrin beta 2 (ITGB2, CD18) and Integrin beta 1 (ITGB1, CD29) (Zurawski & de Vries 1994), MHC class II and ow affinity immunoglobulin epsilon Fc receptor (FCER2, CD23) expression (de Vries 1998). In endothelial cells IL13 induces expression of Vascular cell adhesion protein 1 (VCAM1), which is important in the recruitment of eosinophils (Bochner et al. 1995).
R-HSA-6788571 (Reactome) Characterisation of Signal transducer and activator of transcription 6 (STAT6)-deficient mice suggests that Interleukin-13 (IL13) signaling, like Interleukin-4 (IL4) signaling, uses STAT6 (Takeda et al. 1996, Kaplan et al. 1996). In humans STAT6 is activated in response to IL4 and IL13 (Wang et al. 2004) and can bind tyrosine-phosphorylated Interleukin-4 receptor subunit alpha (IL4R) (Hou et al. 1994, Schindler et al. 1996, Mikita et al. 1998), but in response to IL13, STAT6 binds Interleukin-13 receptor subunit alpha 1 (IL13RA1), to be phosphorylated by Non-receptor associated tyrosine kinase 2 (TYK2) (Bhattacharjee et al. 2013).

Binding and phosphorylation of STAT3 has been reported in response to IL13 (Rahaman et al. 2005, Bhattacharjee et al. 2013) but not IL4 (Friedrich et al. 1999), suggesting that STAT3 binding might depend on IL13RA, but recently STAT3 was reported to associate with IL4R and be phosphorylated by Janus kinase 2 (JAK2) (Umeshita-Suyama et al. 2000, Bhattacharjee et al. 2013).

STAT1 is activated in response to IL13 (Wang et al. 2004) and reported to bind IL13RA1 and be phosphorylated by TYK2 (Bhattacharjee et al. 2013).
R-HSA-6788582 (Reactome) Once bound to the Interleukin-13 (IL13) type II receptor, Signal transducer and activator of transcription 3 (STAT3) is tyrosine phosphorylated by Janus kinase 2 (JAK2), while STAT1 and STAT6 are phosphorylated by Non-receptor tyrosine kinase 2 (TYK2) (Bhattacharjee et al. 2013).
R-HSA-6788622 (Reactome) Phosphorylated Signal transducer and activator of transcription 3 (STAT3) dimerizes after dissociating from the interleukin-19 (IL19) receptor complex (Akira et al. 1994) or Interleukin-22 (IL22) receptor complex (Lagos-Quintana et al. 2003, Sestito et al. 2011).

According to the classical model, phosphorylated Signal transducer and activator of transcription (STAT) monomers associate in an active dimer form, which is stabilized by the reciprocal interactions between a phosphorylated tyrosine residue of one and the SH2 domain of the other monomer (Shuai et al. 1994). These dimers then translocate to the nucleus (Akira et al. 1994). Recently an increasing number of studies have demonstrated the existence of STAT dimers in unstimulated cell states and the capability of STATs to exert biological functions independently of phosphorylation (Braunstein et al. 2003, Li et al. 2008, Santos & Costas-Pereira 2011). As phosphorylation of STATs is not unequivocally required for its subsequent translocation to the nucleus, this event is shown as an uncertain process.
R-HSA-6788623 (Reactome) The classical model of JAK-STAT signaling suggests that phosphorylated Signal transducer and activator of transcription (STAT) translocates to the nucleus (Akira et al. 1994) where it binds DNA to mediate the effects of Interleukin-13 (IL13) on expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, with important consequences for their ability to activate and sustain immune and inflammatory responses.

Recently, STATs have been shown to shuttle freely between the cytoplasm and the nucleus, independent of tyrosine phosphorylation (Liu et al. 2005, Li 2008, Reich 2013). Binding of unphosphorylated STAT3 to DNA has been reported (Nkansah et al. 2013). As it is not clear what triggers nuclear accumulation of STATs in response to IL13, this event is shown as an uncertain process.
R-HSA-6788628 (Reactome) Once phosphorylated, Signal transducer and activator of transcription family members (STATs) dissociate from the receptor complex and translocate to the nucleus.
R-HSA-6789325 (Reactome) IL13 inhibits monocyte and macrophage production of Interleukin-1 (IL1), IL6, IL8, Tumor necrosis factor (TNF) and IL12 (de Vries et al. 1998), through a mechanism that partially involves suppression of Nuclear factor NF-kappa-B.
R-HSA-6789524 (Reactome) In human peripheral blood, monocytes Interleukin-4 (IL4) and Interleukin-13 significantly downregulate the expression of classical proinflammatory signal transducers, such as Interleukin-1 (IL1), Interleukin-6, Interleukin-8, Interleukin-18, C-C motif chemokine 2 (CCL2) and Tumor necrosis factor (TNF). Expression of Prostaglandin G/H synthase 2 (PTGS2, COX2) and Arachidonate 5-lipoxygenase (ALOX5), enzymes involved in the biosynthesis of the proinflammatory eicosanoids, is also attenuated (Chatidis et al. 2005).
This is a black box event because the mechanism of gene regulation is not fully defined.
R-HSA-6789615 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M (OSM), and leukemia inhibitory factor (LIF). Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some have been confirmed as direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014).

Genes for extracellular proteins that are upregulated by STAT3 include Lipopolysaccharide-binding protein (LBP) (Schumann et al. 1996), IL10 (Schaefer et al. 2009), IL23A (Kortylewski et al. 2009), Transforming growth factor beta-1 (TGFB1) (Kinjyo et al. 2006), Matrix metalloproteinase-1 (MMP1, Interstitial collagenase) (Itoh et al. 2006), MMP2 (Xie et al. 2004), MMP3 (Liu et al. 2013), MMP9 (Song et al. 2009), Neutrophil gelatinase-associated lipocalin (LCN2) (Jung et al. 2012, Xu et al. 2015), Pro-opiomelanocortin (POMC) (Bosquet et al. 2000), Serum amyloid A-1 protein (SAA1) (Hagihara et al. 2005), Vascular endothelial growth factor A (VEGFA) (Niu et al. 2002), Fibroblast growth factor 2 (FGF2) (Huang et al. 2013), Hepatocyte growth factor (HGF) (Hung & Elliot 2001), IL17A, IL17F (Durant et al. 2010) and Metalloproteinase inhibitor 1 (TIMP1) (Adamson et al. 2013).
R-HSA-6789960 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes encoding nuclear proteins that are downregulated by STAT3 include Necdin (NDN) (Haviland et al. 2011) and Cellular tumor antigen p53 (TP53) (Niu et al. 2005).
R-HSA-6790022 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes for plasma membrane proteins that are upregulated by STAT3 include Intercellular adhesion molecule 1 (ICAM1) (Scuringa et al. 2001), Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B, TNFR2) (Hamilton et al. 2011), Sphingosine 1-phosphate receptor 1 (S1PR1, EDG1) (Lee et al. 2010), Interleukin-6 receptor subunit alpha (IL6R), Interleukin-23 receptor (IL23R) (Durant et al. 2010) and Mucin-1 (MUC1) (Gaemers et al. 2001).
R-HSA-6790025 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014), including the mitochondrial outer membrane protein genes Apoptosis regulator BCL2 (Bhattacharya et al. 2005) and Bcl-2-like protein 1 (BCL2L1, Bcl-XL) (Catlett-Falcone et al. 1999).
R-HSA-6790029 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014), including the gene which encodes the endoplasmic reticulum membrane protein Prostaglandin G/H synthase 2 (PTGS2, COX2) (Lo et al. 2010).
R-HSA-6790036 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes for nuclear proteins upregulated by STAT3 include CCAAT/enhancer-binding protein delta (CEBPD) (Hutt et al. 2000), B-cell lymphoma 6 protein (BCL6) (Reljic et al. 2000), Myc proto-oncogene protein (MYC) (Kiuchi et al. 1999, Bowman et al. 2001), Proto-oncogene c-Fos (FOS) (Yang et al. 2003), Hypoxia-inducible factor 1-alpha (HIF1A) (Niu et al. 2008), Transcription factor SOX-2 (SOX2) (Foshay & Gallicano 2008), the homeobox protein NANOG (Okumura et al. 2011), Twist-related protein 1 (TWIST1) (Lo et al. 2007, Cheng et al. 2008), Zinc finger E-box-binding homeobox 1 (ZEB1) (Xiong et al. 2012), POU domain, class 2, transcription factor 1 (POU2F1) (OCT1) (Wang et al. 2013), Baculoviral IAP repeat-containing protein 5 (BIRC5, Survivin) (Gritsko et al. 2006), G1/S-specific cyclin-D1 (CCND1) (Leslie et al. 2006), Serine/threonine-protein kinase PIM1 (Przanowski et al. 2014), Forkhead box protein O1 (FOXO1), FOXO3 (Oh et al. 2011), Nuclear receptor ROR-alpha (RORA), RORC, Basic leucine zipper transcriptional factor ATF-like (BATF) (Durant et al. 2010) and Transcription factor JUNB (Coffer et al. 1995).
R-HSA-6790038 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014), including the gene which encodes the endoplasmic reticulum lumen protein Endoplasmin (HSP90B1) (Madamanchi et al. 2001).
R-HSA-6790041 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes for cytoplasmic proteins upregulated by STAT3 include Suppressor of cytokine signaling 3 (SOCS3) (He et al. 2003), Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) (Becker et al. 2014), Heat shock protein HSP 90-alpha (HSP90AA1) (Chen et al. 2007), Fascin (FSCN1) (Snyder et al. 2011), Vimentin (VIM) (Wu et al. 2004), Rho-related GTP-binding protein RhoU (RHOU) (Schiavone et al. 2009), RAC-alpha serine/threonine-protein kinase (AKT1) (Xu et al. 2005), Cyclin-dependent kinase inhibitor 1 (CDKN1A) (Bellido et al. 1998), Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1) (Abell et al. 2005), Signal transducer and activator of transcription 1 (STAT1) (Han et al. 2013), Interferon regulatory factor 4 (IRF4) (Durant et al. 2010) and Nitric oxide synthase, inducible (NOS2) (Lo et al. 2005).
R-HSA-6793958 (Reactome) Phosphorylated Signal transducer and activator of transcription 6 (STAT6) dimers translocate to the nucleus and activate the transcription of several genes. In experimental models, targeted gene disruption of STAT6 inhibited airway hyperresponsiveness, airway inflammation, and fibrosis (Blease et al. 2002). STAT6 promotes transcription of the cell surface proteins Interleukin-4 receptor alpha (IL4R) (Matsukura et al. 1999) and Low affinity immunoglobulin epsilon Fc receptor (FCER2) (Takeda et al. 1994, Park et al. 1998). IL4 links the immune system to the opioid system by inducing transcription of the mu- and delta-opioid receptors (MOR, DOR) (Borner et al. 2004, Kraus et al. 2001) and pro-opiomelanocortin (POMC) (Busch-Dienstfertig et al. 2012). Opioid receptor gene expression in T cells is STAT6-dependent while POMC gene expression in lymphocytes is mediated by STAT3 (Busch-Dienstfertig & González-Rodríguez 2013).
R-HSA-6793975 (Reactome) Phosphorylated Signal transducer and activator of transcription 6 (STAT6) dimers translocate to the nucleus and activate the transcription of several genes including the nuclear protein Trans-acting T-cell-specific transcription factor GATA-3 (Takeda et al. 1994, Park et al. 1998).
R-HSA-6793978 (Reactome) Phosphorylated Signal transducer and activator of transcription 6 (STAT6) dimers translocate to the nucleus and activate the transcription of several genes. In experimental models, targeted gene disruption of STAT6 inhibited airway hyperresponsiveness, airway inflammation, and fibrosis (Blease et al. 2002). STAT6 promotes transcription of the extracellular proteins C-C motif chemokine 11 (CCL11, Eotaxin) (Matsukura et al. 1999), Ig epsilon chain C region (IGHE) (Stütz & Woisetschlager 1999), Ig gamma-1 chain C region (IGHG1) (Warren et al. 1999) and Ig gamma-4 chain C region (IGHG4) (Hebenstreit et al. 2006).
R-HSA-6797245 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes that are downregulated by STAT3 include the extracellular protein Tumor necrosis factor ligand superfamily member 6 (FASLG) (Ivanov et al. 2001).
R-HSA-6797267 (Reactome) In human peripheral blood monocytes Interleukin-4 (IL4) and IL13 significantly upregulates the levels of proteins involved in inflammatory resolution including the cell surface protein CD36 (Berry et al. 2007).
R-HSA-6797268 (Reactome) In human peripheral blood monocytes Interleukin-4 (IL4) and IL13 significantly upregulate the levels of proteins involved in inflammatory resolution, including the ER membrane protein 15-lipoxygenase (ALOX15) (Chaitidis et al. 2005).
R-HSA-6797269 (Reactome) In human peripheral blood monocytes Interleukin-4 (IL4) and IL13 significantly upregulate the levels of proteins involved in inflammatory resolution including the cytoplasmic proteins 15-lipoxygenase (ALOX15) and heat shock protein 8 (HSP8) (Chaitidis et al. 2005, Yakubenko et al. 2011).
R-HSA-6797271 (Reactome) In human peripheral blood monocytes Interleukin-4 (IL4) and IL13 significantly upregulate the levels of proteins involved in inflammatory resolution including the mitochondrial outer membrane protein monoamine oxidase-A (MAOA) (Chaitidis et al. 2005).
R-HSA-6797293 (Reactome) In human peripheral blood, monocytes Interleukin-4 (IL4) and Interleukin-13 significantly downregulate the expression of classical proinflammatory signal transducers, such as Interleukin-1 (IL1), Interleukin-6, Interleukin-8, Interleukin-18, C-C motif chemokine 2 (CCL2) and Tumor necrosis factor (TNF). Expression of Prostaglandin G/H synthase 2 (PTGS2, COX2) and Arachidonate 5-lipoxygenase (ALOX5), enzymes involved in the biosynthesis of the proinflammatory eicosanoids, is also attenuated (Chatidis et al. 2005).
This is a black box event because the mechanism of gene regulation is not fully defined.
R-HSA-9679028 (Reactome) Janus Kinase 3 (JAK3) binds and is inhibited by several small molecule drugs (Clark et al. 2014, Changelian et al. 2003, Flanagan et al. 2010, Dhillon 2017, Chi et al. 2020). The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. Drugs that inhibit these kinases such as baricitinib, tofacitinib, ruxolitinib and tofacitinib are thus plausible candidates for treatment of severe host inflammatory reactions to viral infection (Peterson et al. 2020, Richardson et al. 2020).
SOCS1 geneR-HSA-6785860 (Reactome)
SOCS1ArrowR-HSA-6785860 (Reactome)
SOCS5,(SOCS1)R-HSA-6785821 (Reactome)
STAT1,STAT3,STAT6R-HSA-6788571 (Reactome)
STAT3,STAT6R-HSA-6786124 (Reactome)
STAT3-upregulated cytosolic proteinsArrowR-HSA-6790041 (Reactome)
STAT3-upregulated

extracellular

proteins
ArrowR-HSA-6789615 (Reactome)
STAT3-upregulated

genes for extracellular

proteins
R-HSA-6789615 (Reactome)
STAT3-upregulated

genes for cytosolic

proteins
R-HSA-6790041 (Reactome)
STAT3-upregulated

genes for nuclear

proteins
R-HSA-6790036 (Reactome)
STAT3-upregulated

genes for plasma

membrane proteins
R-HSA-6790022 (Reactome)
STAT3-upregulated nuclear proteinsArrowR-HSA-6790036 (Reactome)
STAT3-upregulated

plasma membrane

proteins
ArrowR-HSA-6790022 (Reactome)
STAT6 upregulated

extracellular

protein genes
R-HSA-6793978 (Reactome)
STAT6 upregulated

extracellular

proteins
ArrowR-HSA-6793978 (Reactome)
STAT6 upregulated

plasma membrane

protein genes
R-HSA-6793958 (Reactome)
STAT6 upregulated

plasma membrane

proteins
ArrowR-HSA-6793958 (Reactome)
TYK2R-HSA-6785762 (Reactome)
p-Y641-STAT6 dimerArrowR-HSA-6785860 (Reactome)
p-Y641-STAT6 dimerArrowR-HSA-6793958 (Reactome)
p-Y641-STAT6 dimerArrowR-HSA-6793975 (Reactome)
p-Y641-STAT6 dimerArrowR-HSA-6793978 (Reactome)
p-Y701-STAT1

dimer,p-Y705-STAT3 dimer,p-Y641-STAT6

dimer
ArrowR-HSA-6788622 (Reactome)
p-Y701-STAT1

dimer,p-Y705-STAT3 dimer,p-Y641-STAT6

dimer
ArrowR-HSA-6788623 (Reactome)
p-Y701-STAT1

dimer,p-Y705-STAT3 dimer,p-Y641-STAT6

dimer
R-HSA-6788623 (Reactome)
p-Y701-STAT1,p-Y705-STAT3,p-Y641-STAT6ArrowR-HSA-6788628 (Reactome)
p-Y701-STAT1,p-Y705-STAT3,p-Y641-STAT6R-HSA-6788622 (Reactome)
p-Y705-STAT3 dimer, p-Y614-STAT6 dimerArrowR-HSA-6786097 (Reactome)
p-Y705-STAT3 dimer, p-Y614-STAT6 dimerR-HSA-6786293 (Reactome)
p-Y705-STAT3 dimer, p-Y641-STAT6 dimerArrowR-HSA-6786293 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6789615 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790022 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790025 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790029 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790036 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790038 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790041 (Reactome)
p-Y705-STAT3 dimerTBarR-HSA-6789960 (Reactome)
p-Y705-STAT3 dimerTBarR-HSA-6797245 (Reactome)
p-Y705-STAT3,p-Y641-STAT6ArrowR-HSA-6786072 (Reactome)
p-Y705-STAT3,p-Y641-STAT6R-HSA-6786097 (Reactome)
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