Interleukin-12 family signaling (Homo sapiens)

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42, 52, 62131937, 5138, 50, 658, 4731, 69474732, 476832, 47471147475740, 60, 644, 10, 49432532, 474710, 303547313028, 59, 6123, 27, 594737, 515415, 36, 58120, 395936, 48, 50, 60, 64472831, 6336, 654, 7, 10, 464718, 24, 41, 6630572910, 302222, 562216, 27, 3459, 6720, 39599, 1025533, 47837, 5137, 511647537, 51cytosolGolgi lumenendoplasmic reticulum lumenlate endosome lumencytosolendoplasmic reticulum lumennucleoplasmIL12B IL12A IL12A IL12B TYK2 STAT3 IL12RB2 p-Y693-STAT4 dimerIL12B IL12RB1 STAT4IL27 IL12B IL12RB1 Gene and proteinexpression byJAK-STAT signalingafterInterleukin-12stimulationSTAT3p-Y701-STAT1 IL12B ADPp-Y705-STAT3 p-Y-IL23R p-Y693-STAT4 p-Y705-STAT3 ADPEBI3 geneEBI3 IL27 TYK2 IL12RB2:JAK2IL12A p-Y705-STAT3 JAK2 IL12RB1:TYK2:IL12RB2:JAK2JAK2 IL12A:IL12BADPp-JAK2 CRLF1:IL27IL12B IL23A IL6ST EBI3 gene IL12RB1 p-Y611-IL27RA IL6ST EBI3 p-Y-TYK2 ATPIL27RA IL12RB1 p-Y705-STAT3:p-Y693-STAT4p-JAK2 JAK2 STAT1 p-Y701-STAT1 IL27p-STAT4 IL12A:EBI3STAT4 EBI3ADPp-Y701-STAT1 IL27RA p-STAT1 2xIL12BEBI3 IL12A IL12B:IL23AJAK2 p-JAK1 p-JAK2 IL12A IL6ST:JAK1, JAK2,(TYK2)p-Y693-STAT4 EBI3 IL12A:IL12B:IL12RB1:p-Y-TYK2:IL12RB2:p-JAK2IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2IL6ST IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3:STAT4p-STAT4 IL12A STAT4IL27:EBI3STAT1 IL35:(IL12RB2:p-JAK2) dimerJAK2 p-JAK2 IL27 p-Y705-STAT3IL12AIL12RB1 p-Y693-STAT4IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2p-Y705-STAT3:p-Y693-STAT4CANXp-Y701-STAT1 IL12A p-STAT1 EBI3 p-Y-IL23R IL12A ATPEBI3 STAT3 p-JAK1 p-JAK2 IL12RB2 CANX IL23A IL35:IL6ST:JAK1:IL12RB2:JAK2IL12RB2 IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3IL27IL12A gene TYK2 p-JAK1 EBI3 IL12RB1 IL27RA IL12B p-Y-IL6ST TYK2 IL12B IL12B p-JAK2 ATPTYK2 IL12RB2 p-STAT3 p-JAK1 IL12RB2 p-JAK1 p-Y693-STAT4 p-JAK2 TYK2 p-Y-IL23R VAMP7IL6ST EBI3 JAK2 IL12RB1 EBI3 EBI3 EBI3 IL12A IL12A ADPp-Y693-STAT4 IL12B JAK2 p-Y693-STAT4 IL23A CANX EBI3 IL27 IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2p-JAK1 IL23A EBI3 IL23Rp-Y-TYK2 IL12A IL23A ADPEBI3 sIL27RAIL23A IL23A EBI3 ATPp-JAK1 EBI3 IL12RB1 p-Y693-STAT4 IL35:(IL12RB2:p-JAK2) dimer:p-STAT4IL6ST p-Y611-IL27RA TYK2 p-Y701-STAT1:p-Y705-STAT3:IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2ADPATPJAK2 IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT3p-JAK2 CANX:EBI3:IL12Ap-JAK1 IL6STIL6ST p-JAK1 IL12A IL12A ATPJAK1 IL12RB1 ATPIL12A TYK2 STAT4 IL12B p-Y800-IL12RB2 p-Y800-IL12RB2 IL12RB1 IL12RB2 IL27 ADPIL35:(IL6ST:p-JAK1:p-JAK2:p-TYK2) dimerIL-35:(IL6ST:p-JAK1:p-JAK2) dimer:p-STAT1IL35p-Y-IL23R p-JAK1 ADPIL12A IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2Y963-STAT4 dimerIL12RB1:TYK2JAK1 p-Y693-STAT4:p-Y701-STAT1EBI3 JAK2ATPSTAT4 IL12RB1 EBI3 CANX IL12A IL35:(IL12RB2:p-JAK2) dimer:STAT4IL12A p-Y693-STAT4 p-TYK2 IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2:2xSTAT4IL27RA TYK2 EBI3 STAT4 p-Y701-STAT1 IL27RA JAK2 IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT4IL-35:(IL6ST:p-JAK1:p-JAK2) dimerATPp-JAK2 IL27 p-JAK2 IL12RB2IL23R ADPJAK1 STAT3CRLF1 ADPIL-35:IL27RA:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT3p-JAK2 IL27RA IL12A JAK2 p-JAK2 IL12B ADPATPp-JAK2 p-JAK2 IL12B TYK2 CANX:EBI3:IL27p-Y701-STAT1p-Y-TYK2 JAK1 p-Y705-STAT3 STAT1 CANX:EBI3TYK2 IL12RB1 IL12RB2 STAT3IL12B JAK1 IL12A IL12A:IL12BSTAT1TYK2 sIL27RAJAK2p-Y705-STAT3IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2p-JAK2 IL12Ap-JAK2 IL27 IL6ST IL12B:IL23AEBI3 p-JAK2 IL12B IL12A p-TYK2 STAT3 EBI3 ADPp-TYK2 JAK2 IL27IL6ST EBI3 p-Y701-STAT1 IL12Bp-JAK2 IL12RB1 EBI3 IL12RB2 EBI3EBI3 IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:p-Y705-STAT3:p-Y693-STAT4EBI3 IL12RB2 IL12RB2 IL12B IL23R IL12RB2 IL27:EBI3IL23A 2xp-Y693-STAT4:IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2EBI3 IL27 p-Y693-STAT4:p-Y701-STAT1:EBI3 genep-JAK2 JAK1 p-Y693-STAT4 p-STAT3p-JAK2 IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT4p-JAK2 p-Y611-IL27RA 2xIL27RAIL12RB2 p-STAT4IL23A:IL12B:IL23R:JAK2:IL12RB1:TYK2IL27 JAK1 ADPp-Y693-STAT4:p-Y701-STAT1:IL12A geneJAK1 IL23R:JAK2JAK2 IL12A:IL12BATPp-Y693-STAT4 ATPIL12B p-Y705-STAT3 STAT1 IL12BIL-35:(IL6ST:JAK1:JAK2) dimerEBI3 p-STAT1 p-Y701-STAT1:p-Y705-STAT3p-JAK1 ATPIL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2IL35:IL27RA:JAK1:IL12RB2:JAK2CRLF1:IL27p-JAK1 JAK1 IL12A geneIL6ST p-JAK2 TYK2ATPSTAT4IL12A:IL12BIL35:IL6ST:p-JAK1:IL12RB2:p-JAK2IL12A CRLF1 IL-35:(IL6ST:p-JAK1:p-JAK2) dimer: STAT1IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3IL12RB2 p-Y-IL6ST p-STAT4 IL12A P4HBIL6ST p-Y-TYK2 p-Y800-IL12RB2 IL27RA:JAK1IL12RB2 p-JAK2 IL12B ATPATPJAK1, JAK2, (TYK2)EBI3 JAK1 IL6ST p-JAK2 IL12RB2 IL12B STAT3 2xIL12BSTAT1IL12A ADPIL12A p-JAK2 TYK2 p-Y-TYK2 p-Y-IL6ST p-STAT1 p-Y701-STAT1:p-Y705-STAT3IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)IL27RAATPIL12A JAK2 ADPIL23ACRLF1p-Y705-STAT3 IL12RB2 IL27:EBI3:IL27RA:p-JAK1:IL6ST:p-JAK1,p-JAK2,p-TYK2IL12A IL35:(IL12RB2:JAK2dimer)p-STAT1TYK2 IL23R IL12RB1 IL12BIL12A p-JAK1 p-TYK2 STAT4IL12B IL27RA IL12A p-TYK2 p-Y693-STAT4ADPIL12A IL6ST IL12A IL27 p-STAT1:p-STAT4IL23A:IL12B:IL12RB1:p-TYK2:IL23R:p-JAK2IL12RB2 EBI3 p-JAK1 IL27RA p-JAK2 JAK1IL12RB1222253, 64, 6810295222269113682, 82922576332, 82, 17, 4522636586, 1155132, 882, 824722810, 4427142727224112228635522345563295965222, 8571082, 8552, 85723, 27, 5929632, 810103, 52, 82, 82, 55636365652, 8226338, 50, 6522632222516362, 81022572210, 261010, 30101010292, 86340, 642210, 3055636310310296339291022121658636422225721342, 8


Description

Interleukin-12 (IL-12) is a heterodimer of interleukin-12 subunit alpha (IL12A, IL-12p35) and interleukin-12 subunit beta (IL12B, IL-12p40). It is a potent immunoregulatory cytokine involved in the generation of cell mediated immunity to intracellular pathogens. It is produced by antigen presenting cells, including dendritic cells, macrophages/monocytes, neutrophils and some B cells (D'Andrea et al. 1992, Kobayashi et al.1989, Heufler et al.1996). It enhances the cytotoxic activity of natural killer (NK) cells and cytotoxic T cells, stimulating proliferation of activated NK and T cells and induces production of interferon gamma (IFN gamma) by these cells (Stern et al. 1990). IL-12 also plays an important role in immunomodulation by promoting cell mediated immunity through induction of a class 1 T helper cell (Th1) immune response. IL-12 may contribute to immunopathological conditions such as rheumatoid arthritis (McIntyre et al. 1996).

The receptor for IL-12 is a heterodimer of IL-12Rbeta1 (IL12RB1) and IL-12Rbeta2 (IL12RB2), both highly homologous to Interleukin-6 receptor subunit beta (IL6ST,gp130). Each has an extracellular ligand binding domain, a transmembrane domain and a cytosolic domain containing box 1 and box 2 sequences that mediate binding of Janus family tyrosine kinases (JAKs). IL-12 binding is believed to bring about the heterodimerization and generation of a high affinity receptor complex capable of signal transduction. In this model, receptor dimerization leads to juxtaposition of the cytosolic domains and subsequent tyrosine phosphorylation and activation of JAK2 and TYK2. These activated kinases, in turn, tyrosine phosphorylate and activate several members of the signal transducer and activator of transcription (STAT) family, mainly STAT4, while also STAT1, STAT3 and STAT5 have been reported to be activated (Bacon et al. 1995, Jacobson et al. 1995, Yu et al. 1996, Gollob et al.1995). The STATs translocate to the nucleus to activate transcription of several genes, including IFN gamma. The production of IFN gamma has a pleiotropic effect in the cell, stimulating production of molecules important to cell mediated immunity. In particular, IFN gamma stimulates production of more IL-12 and sets up a positive regulation loop between IL-12 signaling and IFN gamma (Chan et al. 1991). The importance of IL-12 for this loop is demonstrated by IL-12 and STAT4 knockout mice that are severely compromised in IFN-gamma production (Kaplan et al. 1996; Magram et al. 1996), as well as by patients with IL12B mutations that are severely compromised in IFN-gamma production (Altare et al.1998).

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Reactome Author: Jupe, Steve

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  64. Aparicio-Siegmund S, Moll JM, Lokau J, Grusdat M, Schröder J, Plöhn S, Rose-John S, Grötzinger J, Lang PA, Scheller J, Garbers C.; ''Recombinant p35 from bacteria can form Interleukin (IL-)12, but Not IL-35.''; PubMed Europe PMC Scholia
  65. Alloza I, Vandenbroeck K.; ''The metallopeptide antibiotic bacitracin inhibits interleukin-12 alphabeta and beta2 secretion.''; PubMed Europe PMC Scholia
  66. Boniface K, Blom B, Liu YJ, de Waal Malefyt R.; ''From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited.''; PubMed Europe PMC Scholia
  67. Rosengren AT, Nyman TA, Lahesmaa R.; ''Proteome profiling of interleukin-12 treated human T helper cells.''; PubMed Europe PMC Scholia
  68. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA.; ''Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.''; PubMed Europe PMC Scholia
  69. Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ.; ''Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes.''; PubMed Europe PMC Scholia

History

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115018view16:55, 25 January 2021ReactomeTeamReactome version 75
113463view11:54, 2 November 2020ReactomeTeamReactome version 74
112663view16:05, 9 October 2020ReactomeTeamReactome version 73
101579view11:44, 1 November 2018ReactomeTeamreactome version 66
101115view21:28, 31 October 2018ReactomeTeamreactome version 65
100643view20:02, 31 October 2018ReactomeTeamreactome version 64
100193view16:47, 31 October 2018ReactomeTeamreactome version 63
99744view15:13, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99309view12:46, 31 October 2018ReactomeTeamreactome version 62
93321view11:20, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2xIL12BComplexR-HSA-8950291 (Reactome) Interleukin-12 subunit beta can homodimerize with other equal subunit. This homodimer can be stabilized by mean of protein disulfide isomerase which create a disulfide binding between both subunits in the endoplasmic reticulum(PMID:11054122).
2xIL12BComplexR-HSA-8950640 (Reactome) Homodimeric protein of Interleukin-12 beta subunit (IL12B or IL12p40) can be secreted to exert its inhibitory function over Interleukin-12 heterodimer interleukin-12 receptor interaction. The secretion has been shown experimentally in COS cells and by mean of ELISA assays (PMID: 7527811).
2xIL27RAComplexR-HSA-8950332 (Reactome)
2xp-Y693-STAT4:IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2ComplexR-HSA-8952795 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CANX ProteinP27824 (Uniprot-TrEMBL)
CANX:EBI3:IL12AComplexR-HSA-8950383 (Reactome)
CANX:EBI3:IL27ComplexR-HSA-8950465 (Reactome)
CANX:EBI3ComplexR-HSA-8950369 (Reactome) Calnexin (CANX or p95 calnexin) binds Interleukin-27 subunit beta (EBI3, IL27B). In human cell lines (BL30, BL41, Louckes, BJAB, P3HR1) most newly synthesized EBI3 is retained in the endoplasmic reticulum (ER) in an endoglycosidase H-sensitive form (Devergne et al. 1996, 1997), bound to CANX and a 60-kDa protein and transiently with a p75-kDa protein, both ignored here). EBI3 can be released by itself but the association with CANX prevents this, the complex is retained in the ER. The co-expression of other interleukin subunits enables the release of EBI3 in a complex with Interleukin-27 subunit alpha (IL27) (Devergne et al. 1996).
CANXProteinP27824 (Uniprot-TrEMBL)
CRLF1 ProteinO75462 (Uniprot-TrEMBL)
CRLF1:IL27ComplexR-HSA-8950600 (Reactome)
CRLF1:IL27ComplexR-HSA-8950767 (Reactome) Interleukin 27 alpha subunit (IL27,IL27A, IL27p28) and Cytokine like factor 1 (CRLF1) form a secreted complex. Secretion of IL27 was observed in HEK 293 cells transfected with IL27 cDNA in the absence of CRLF1. This may indicate that formation of a complex is not strictly required for IL27 secretion in these cells. Alternatively it could reflect the formation of a complex between IL27 and endogenous CRLF1, which is expressed in HEK 293 cells. The IL27:CRLF1 complex is biologically active (Crabé et al. 2009).

This reaction is a black box event because the mechanism of translocation is unknown.
CRLF1ProteinO75462 (Uniprot-TrEMBL)
EBI3 ProteinQ14213 (Uniprot-TrEMBL) Interleukin-27 subunit beta (EBI3) can be founded accumulated in the endoplasmic reticlum binded to Calnexin (PMID:9342359)
EBI3 gene ProteinENSG00000105246 (Ensembl)
EBI3 geneGeneProductENSG00000105246 (Ensembl)
EBI3ProteinQ14213 (Uniprot-TrEMBL) Interleukin-27 subunit beta (EBI3) can be founded accumulated in the endoplasmic reticlum binded to Calnexin (PMID:9342359)
Gene and protein

expression by JAK-STAT signaling after Interleukin-12

stimulation
PathwayR-HSA-8950505 (Reactome) Experiments using human cord blood CD4(+) T cells show 22 protein spots and 20 protein spots, upregulated and downregulated proteins respectively, following Interleukin-12 stimulation (Rosengren et.al, 2005). The identified upregulated proteins are: BOLA2, PSME2, MTAP, CA1, GSTA2, RALA, CNN2, CFL1, TCP1, HNRNPDL, MIF, AIP, SOD1, PPIA and PDCD4.
And the identified downregulated proteins are:
ANXA2, RPLP0, CAPZA1, SOD2, SNRPA1, LMNB1, LCP1, HSPA9, SERPINB2, HNRNPF, TALDO1, PAK2, TCP1, HNRNPA2B1, MSN, PITPNA, ARF1, SOD2, ANXA2, CDC42, RAP1B and GSTO1.
IL-35:(IL6ST:JAK1:JAK2) dimerComplexR-HSA-8983525 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer: STAT1ComplexR-HSA-8983842 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer:p-STAT1ComplexR-HSA-8983844 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimerComplexR-HSA-8983843 (Reactome)
IL-35:IL27RA:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT3ComplexR-HSA-8984010 (Reactome)
IL12A ProteinP29459 (Uniprot-TrEMBL)
IL12A gene ProteinENSG00000168811 (Ensembl)
IL12A geneGeneProductENSG00000168811 (Ensembl)
IL12A:EBI3ComplexR-HSA-8950589 (Reactome) Interleukin-35 is a heterodimer of Interleukin-27 subunit beta (EBI3) and Interleukin-12 subunit alpha (IL12A or IL12-p35) (Devergne et al. 1997). It is required for maximal T regulatory cell activity (Collison et al. 2007).
Site directed mutagenesis of IL12A identified mutations that disrupt formation of Interleukin 12 and Interleukin 27 heterodimeric complexes but not Interleukin 35. IL12A appears to pair with EBI3 entirely differently from IL27. (Jones et al. 2012). In the absence of IL12A, EBI3 is retained in the endoplasmic reticulum, associated with the chaperone Calnexin (CANX) (Devergne et al. 1997).
This is a Black Box event because we know that EBI3 is retained as a complex with CANX and the co expression of EBI3 and IL12A enables their secretion, but we don't have evidence about the mechanism of dissociation of CANX from EBI3 (Devergne et al. 1997).

IL12A:IL12B:IL12RB1:p-Y-TYK2:IL12RB2:p-JAK2ComplexR-HSA-8950227 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2:2xSTAT4ComplexR-HSA-8950379 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2ComplexR-HSA-8950686 (Reactome)
IL12A:IL12BComplexR-HSA-447102 (Reactome)
IL12A:IL12BComplexR-HSA-8950122 (Reactome) The Interleukin-12 heterodimer (IL-12) is formed by Interleukin-12 subunit alpha (IL12A, IL-12p35) and Interleukin-12 subunit beta (IL12B, IL-12p40) (Podlaski et al. 1992, Kobayashi et al. 1989, Stern et al.1990). Heterodimerization occurs due to charged residue interactions (Yoon et al. 2000) and is stabilized by disulfide bounding.
IL12 heterodimerization is believed to occur in the endoplasmic reticulum (ER) because inhibition of the enzyme Prolyl 4-hydroxylase subunit beta (P4HB), referred to in this article as Protein disulfide isomerase (PDI), by bacitracin causes IL-12 retention in the ER (Alloza & Vandenbroek 2005).
IL12A:IL12BComplexR-HSA-8950228 (Reactome) Inferred from mouse :
Interleukin-12, (IL12) formed from Interleukin-12 subunit alpha (IL12A) and Interleukin-12 subunit beta (IL12B), has been localized intracellularly in late endocytic vesicles expresing the marker protein termed Vesicle-associated membrane protein 7 (VAMP7) (Chiaruttini et al. 2016).

This reaction is a black box event because we do not fully understand the mechanism of translocation.
IL12A:IL12BComplexR-HSA-8950694 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2ComplexR-HSA-8950116 (Reactome) Transfected COS cells express the Interleukin-12 receptor subunit both as monomers, and the dimerization or oligomerization of both receprots does not depend on Interleukin-12 binding. Anyway if Interleukin-12 is prebound to these cells, the resulting banding pattern does not change (PMID:7911493)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2ComplexR-HSA-8981056 (Reactome) Transfected COS cells express the Interleukin-12 receptor subunit both as monomers, and the dimerization or oligomerization of both receprots does not depend on Interleukin-12 binding. Anyway if Interleukin-12 is prebound to these cells, the resulting banding pattern does not change (PMID:7911493)
IL12AProteinP29459 (Uniprot-TrEMBL)
IL12B ProteinP29460 (Uniprot-TrEMBL)
IL12B:IL23AComplexR-HSA-447217 (Reactome)
IL12B:IL23AComplexR-HSA-8950275 (Reactome) Interleukin-23 heterodimer is formed by Interleukin-23 subunit alpha (IL23p19 or p19 or IL23A) and Interleukin-12 subunit beta (IL12B or p40 or IL12p40). Binding of p19 to p40 is mediated primarily by an arginine residue on helix D of p19 that forms an extensive charge and hydrogen-bonding netwrok with residues at the base of a pocket on p40. (PMID: 18680750) This dimer can be retained in the Endoplasmic reticulum upon TFM-C (4-trifluoromethyl-celecobix) treatment (PMID:20054003)
IL12BProteinP29460 (Uniprot-TrEMBL) Interleukin-12 subunit beta have to be in the reticuum where it suffers processing by the PDI enzyme if it is going to homodimerize or heterodimerize with other subunits as Interleukin-23 alpha subunit (PMID:15720785)
IL12RB1 ProteinP42701 (Uniprot-TrEMBL)
IL12RB1:TYK2:IL12RB2:JAK2ComplexR-HSA-8950052 (Reactome) Experimental evidence shows that human IL-12Rbeta2, similar to human IL12Rbeta1, appears to exist at the cell surface as a disulfide bonded dimer/oligomer. Formation of this human Interleukin-12Rbeta2 oligomer is not dependent on Interleukin-12 binding, since it was observed in cells that were never exposed to Interleukin-12 heterodimeric protein.
Interleukin-12 receptor beta1 does not contain any cytoplasmic tyrosine residues, whereas the cytoplasmic region of Interleulin-12 receptor beta2 contains three tyrosine residues. This last has an important role for the beta 2 subunit in Interleukin-12 signal transduction (PMID: 8943050). Based on (Kotenko et. al., 1996, PMID: 8663414) signal transduction receptor chains can be divided into two classes. IL12RB2 would be of the first class : signal transducers (ST) with STAT (or SH2 domain-containg proteins) recruitment sites (SRS) and Jak association sites (JAS) . Whereas IL12RB1 would be the the second class: helper receptors (HR) containg only JAS and no SRS (PMID:27193299 )
IL12RB1:TYK2ComplexR-HSA-8950046 (Reactome) The intracellular domain of human Interleukin-12 receptor subunit beta-1 (IL12RB1) but not the intracellular domain of Interleukin-12 receptor subunit beta-2 (IL12RB2) interacts directly with Non-receptor tyrosine-protein kinase (TYK2) (Zou et al. 1997)
Inferred from mouse:
TYK2 associates with IL12RB1. In the absence of TYK2, IL12RB1 can associate with Tyrosine-protein kinase JAK1 (JAK1) (Floss et al. 2016).
IL12RB1ProteinP42701 (Uniprot-TrEMBL)
IL12RB2 ProteinQ99665 (Uniprot-TrEMBL)
IL12RB2:JAK2ComplexR-HSA-8950039 (Reactome) Inferred from mouse and muse-human protein interaction: There is experimental evidence that show that murine protein Tyrosin kinase Jak2(Jak2) (PMID: 9001223) associates with IL-12Rbeta2 (Interleukin-12 recetor subunit beta 2) directly and IL-12Rbeta1(Interleukin-12 recetor subunit beta 1) and Tyk2(Non-receptor tyrosine-protein kinase TYK2) are not required for the association between IL-12Rbeta2 and Jak2. (PMID:27193299)Stimulation with rhIL-12(recombinant human Interleukin-12) didn’t alter the association between IL-12Rbeta2 and Jak2 in COS 7 cells expressing IL-12Rbeta2, IL-12Rbeta1, Jak2 and Tyk2 (PMID:10198225) In conclusion the amino-terminus of Jak2 is necessary for association with IL-12Rbeta2. Thus Jak2 binds to the cytoplasmatic membrane-proximal region of IL-12Rbeta2, and box2 motif and tyrosine residues in the cytoplasmic domain are not required for binding (PMID:10198225)
IL12RB2ProteinQ99665 (Uniprot-TrEMBL)
IL23A ProteinQ9NPF7 (Uniprot-TrEMBL)
IL23A:IL12B:IL12RB1:p-TYK2:IL23R:p-JAK2ComplexR-HSA-8950239 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3:STAT4ComplexR-HSA-8952752 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3ComplexR-HSA-8950547 (Reactome) Signal transducer and activator of transcription 3 (Stat3) binds Interleukin-23 receptor (Il23r), after cytokine-receptor interaction, for both canonical and non-canonical Stat3 activation (Dumoutier et al. 2009, Floss et al. 2013). This is a black box event because Stat3 binding as a consequence of Interleukin-23 stimulation has not been directly demonstrated.
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:p-Y705-STAT3:p-Y693-STAT4ComplexR-HSA-8952748 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2ComplexR-HSA-8950186 (Reactome)
IL23A:IL12B:IL23R:JAK2:IL12RB1:TYK2ComplexR-HSA-447186 (Reactome)
IL23AProteinQ9NPF7 (Uniprot-TrEMBL) Interleukin-12 and Interleukin-23 heterodimeric proteins can be founded in Endoplasmic reticulum when its secretion is inhibited by celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) (PMID:20054003)
IL23R ProteinQ5VWK5 (Uniprot-TrEMBL)
IL23R:JAK2ComplexR-HSA-8950151 (Reactome)
IL23RProteinQ5VWK5 (Uniprot-TrEMBL)
IL27 ProteinQ8NEV9 (Uniprot-TrEMBL)
IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)ComplexR-HSA-448431 (Reactome) Interleukin-27 (IL27) is an heterodimer composed by (IL27) and (EBI3). It binds to Interleukin-27 heterodimer, formed by Interleukin-27 receptor subunit alpha (IL27RA) and Interleukin-6 receptor subunit beta (IL6ST or gp130). Also in absence of IL27RA it can binds to the Interleukin-6 receptor subunit (IL6ST or gp130) but with lower affinity than to IL27 receptor heterodimer (PMID: 27119567)
IL27:EBI3:IL27RA:p-JAK1:IL6ST:p-JAK1,p-JAK2,p-TYK2ComplexR-HSA-8950252 (Reactome) Interleukin 27 phosphorylates/activates Tyrosine protein kinase JAK2 (JAK2) , non receptor tyrosine protein kinase TYK2 (TYK2) and Tyrosine protein kinase JAK1 (JAK1) (Kanda & Watanabe 2008). JAK1 interacts with IL27RA (Takeda et al 2003 )
As the phosphorylation required for Interleukin 27 induced activation are not clear, this is represented here as a black box event.
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2ComplexR-HSA-8950331 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3ComplexR-HSA-8950267 (Reactome)
IL27:EBI3ComplexR-HSA-448442 (Reactome) There is evidence that shows that when Interleukin-27 subunit beta (EBI3) coexpress with human Interleukin-27 subunit alpha while both can be secreted as a soluble complex (PMID:12121660)
Considering that cells expressing EBI3 keep this protein in the endoplasmic reticulum associated with calnexin, is suggested that subsequent processing and secretion to the extracellular region of EBI3 might be dependent on association with a second subunit, as Interleukin-27 subunit alpha (PMID : 9342359).
IL27:EBI3ComplexR-HSA-8950372 (Reactome) Interleukin27 complex formation
Interleukin 27 subunit beta(EBI3) is expressed in cells and accumulated in the endoplasmic reticulum and associated with the molecular chaperone calnexin (PMID:9342359)

Computational and biological analyses of the IL-27 binding site 1 to its receptor revealed important structural proximities with the ciliary neurotrophic factor group of cytokines and highlighted the contribution of p28Trp97, as well as of EBI3 Phe97, Asp210, and Glu159, as key residues in the interactions between both cytokine subunits (PMID: 20974977)


IL27ProteinQ8NEV9 (Uniprot-TrEMBL)
IL27RA ProteinQ6UWB1 (Uniprot-TrEMBL)
IL27RA:JAK1ComplexR-HSA-8950163 (Reactome)
IL27RAProteinQ6UWB1 (Uniprot-TrEMBL)
IL35:(IL12RB2:JAK2 dimer)ComplexR-HSA-8983520 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:STAT4ComplexR-HSA-8983881 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:p-STAT4ComplexR-HSA-8983877 (Reactome)
IL35:(IL12RB2:p-JAK2) dimerComplexR-HSA-8983873 (Reactome)
IL35:(IL6ST:p-JAK1:p-JAK2:p-TYK2) dimerComplexR-HSA-8985441 (Reactome)
IL35:IL27RA:JAK1:IL12RB2:JAK2ComplexR-HSA-8983989 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT3ComplexR-HSA-8983998 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2ComplexR-HSA-8985392 (Reactome)
IL35:IL6ST:JAK1:IL12RB2:JAK2ComplexR-HSA-6809138 (Reactome) Interleukin-35(IL-35) ,a heterodimer composed by Interleukin-12 subunit beta and Interleukin-27 subunit alpha, signals through IL-12R beta2(IL12RB2) and Interleukin-27 receptor alpha(IL-27RA) in B cells, activating signal transducer and activator of transcription 1(STAT1) and signal transducer and activator of transcription 3(STAT3).
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT4ComplexR-HSA-8952783 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT4ComplexR-HSA-8952780 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2ComplexR-HSA-8950255 (Reactome)
IL35ComplexR-HSA-622267 (Reactome) Interleukin-35 can be secreted(PMID: 9342359) and be detected extracellularly and detected in serum samples as in comparative studies inRehumatoid arthritis (PMID: 26370008)
IL6ST ProteinP40189 (Uniprot-TrEMBL)
IL6ST:JAK1, JAK2, (TYK2)ComplexR-HSA-1067690 (Reactome)
IL6STProteinP40189 (Uniprot-TrEMBL)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK1, JAK2, (TYK2)ComplexR-HSA-1067656 (Reactome)
JAK1ProteinP23458 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
JAK2ProteinO60674 (Uniprot-TrEMBL)
P4HBProteinP07237 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1ProteinP42224 (Uniprot-TrEMBL)
STAT3 ProteinP40763 (Uniprot-TrEMBL)
STAT3ProteinP40763 (Uniprot-TrEMBL)
STAT4 ProteinQ14765 (Uniprot-TrEMBL)
STAT4ProteinQ14765 (Uniprot-TrEMBL)
TYK2 ProteinP29597 (Uniprot-TrEMBL)
TYK2ProteinP29597 (Uniprot-TrEMBL)
VAMP7ProteinP51809 (Uniprot-TrEMBL)
Y963-STAT4 dimerComplexR-HSA-8950759 (Reactome)
p-JAK1 ProteinP23458 (Uniprot-TrEMBL) The receptor chains are also utilized by multiple cytokines (Fig. 1)1,2. IL-12 signals via IL12Rβ1 and IL12Rβ248,71,72, while IL-23 signals through IL12Rβ1 and IL23R69,73. In contrast, IL-27 utilizes gp130 and WSX-174, while IL-35 signals via gp130 and IL12Rβ228. IL-35 is unusual in that it can also signals via two additional receptor chain compositions; gp130-gp130 and IL12Rβ2-lL12Rβ2 homodimers28.
Signaling via all of these receptors is mediated by members of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) family27,75,76 (Fig. 1). JAK2 and either JAK1 or TYK2 appear to mediate phosphorylation of the IL-12 cytokine receptors family-associated STATs. IL-12 mediates signaling via pSTAT477, IL-23 via pSTAT3 and pSTAT469,73, IL-27 via pSTAT1 and pSTAT378,79, and IL-35 via pSTAT1 and pSTAT428. For IL-35, formation of a STAT1:STAT4 heterodimer is required for Ebi2/ Il12a transcription, but partially dispensable for supression28 (PMID:22814351)
p-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-STAT1:p-STAT4ComplexR-HSA-8950747 (Reactome)
p-STAT1ProteinP42224 (Uniprot-TrEMBL)
p-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-STAT3ProteinP40763 (Uniprot-TrEMBL)
p-STAT4 ProteinQ14765 (Uniprot-TrEMBL)
p-STAT4ProteinQ14765 (Uniprot-TrEMBL)
p-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y-IL23R ProteinQ5VWK5 (Uniprot-TrEMBL)
p-Y-IL6ST ProteinP40189 (Uniprot-TrEMBL)
p-Y-TYK2 ProteinP29597 (Uniprot-TrEMBL)
p-Y611-IL27RA ProteinQ6UWB1 (Uniprot-TrEMBL)
p-Y693-STAT4 ProteinQ14765 (Uniprot-TrEMBL)
p-Y693-STAT4 dimerComplexR-HSA-8950602 (Reactome)
p-Y693-STAT4:p-Y701-STAT1:EBI3 geneComplexR-HSA-9015018 (Reactome)
p-Y693-STAT4:p-Y701-STAT1:IL12A geneComplexR-HSA-9015016 (Reactome)
p-Y693-STAT4:p-Y701-STAT1ComplexR-HSA-8950182 (Reactome) Interleukin-35 (IL-35) uses a unique Signal transducer and activator of transcription 1-alpha/beta - Signal transducer and activator of transcription 4 (STAT1:STAT4) heterodimer (Collinson et al. 2012) for signaling. Several cytokine receptors activate STAT1 and STAT4 to drive proinflammatory T helper 1 type responses, so it is unclear how their activation via the interleukin-35 receptor gives rise to a unique STAT dimer.
T cells stimulated with Interleukin-12 plus IFN-gamma (IFNG) induce minimal interaction of a STAT1:STAT4 with consensus STAT-binding sites in the IL12A and EBI3 promoters. However, T cells stimulated with Interleukin-35 showed considerable enrichment for the binding of STAT1 and STAT4 to IL12A position 250 and EBI3 position 500, as well as other sites in their promoters.
This reaction is presented as a black box because the exact mechanism of traslocation to the nucleus is unclear.
p-Y693-STAT4ProteinQ14765 (Uniprot-TrEMBL)
p-Y701-STAT1 ProteinP42224 (Uniprot-TrEMBL)
p-Y701-STAT1:p-Y705-STAT3:IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2ComplexR-HSA-8952746 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ComplexR-HSA-1112590 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ComplexR-HSA-8980551 (Reactome)
p-Y701-STAT1ProteinP42224 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3:p-Y693-STAT4ComplexR-HSA-8950427 (Reactome)
p-Y705-STAT3:p-Y693-STAT4ComplexR-HSA-8950501 (Reactome)
p-Y705-STAT3ProteinP40763 (Uniprot-TrEMBL)
p-Y800-IL12RB2 ProteinQ99665 (Uniprot-TrEMBL)
sIL27RAProteinQ6UWB1 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2xIL12BArrowR-HSA-8950410 (Reactome)
2xIL12BArrowR-HSA-8950456 (Reactome)
2xIL12BR-HSA-8950410 (Reactome)
2xIL12BTBarR-HSA-447226 (Reactome)
2xIL27RAArrowR-HSA-8950766 (Reactome)
2xp-Y693-STAT4:IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2ArrowR-HSA-8950354 (Reactome)
2xp-Y693-STAT4:IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2R-HSA-8952807 (Reactome)
ADPArrowR-HSA-8950269 (Reactome)
ADPArrowR-HSA-8950340 (Reactome)
ADPArrowR-HSA-8950354 (Reactome)
ADPArrowR-HSA-8950364 (Reactome)
ADPArrowR-HSA-8950405 (Reactome)
ADPArrowR-HSA-8950423 (Reactome)
ADPArrowR-HSA-8950453 (Reactome)
ADPArrowR-HSA-8950485 (Reactome)
ADPArrowR-HSA-8950537 (Reactome)
ADPArrowR-HSA-8950591 (Reactome)
ADPArrowR-HSA-8950757 (Reactome)
ADPArrowR-HSA-8983834 (Reactome)
ADPArrowR-HSA-8983835 (Reactome)
ADPArrowR-HSA-8983870 (Reactome)
ADPArrowR-HSA-8983872 (Reactome)
ADPArrowR-HSA-8984012 (Reactome)
ADPArrowR-HSA-8984014 (Reactome)
ATPR-HSA-8950269 (Reactome)
ATPR-HSA-8950340 (Reactome)
ATPR-HSA-8950354 (Reactome)
ATPR-HSA-8950364 (Reactome)
ATPR-HSA-8950405 (Reactome)
ATPR-HSA-8950423 (Reactome)
ATPR-HSA-8950453 (Reactome)
ATPR-HSA-8950485 (Reactome)
ATPR-HSA-8950537 (Reactome)
ATPR-HSA-8950591 (Reactome)
ATPR-HSA-8950757 (Reactome)
ATPR-HSA-8983834 (Reactome)
ATPR-HSA-8983835 (Reactome)
ATPR-HSA-8983870 (Reactome)
ATPR-HSA-8983872 (Reactome)
ATPR-HSA-8984012 (Reactome)
ATPR-HSA-8984014 (Reactome)
CANX:EBI3:IL12AArrowR-HSA-8950362 (Reactome)
CANX:EBI3:IL12AR-HSA-8950740 (Reactome)
CANX:EBI3:IL27ArrowR-HSA-8950342 (Reactome)
CANX:EBI3:IL27R-HSA-8950398 (Reactome)
CANX:EBI3ArrowR-HSA-8950387 (Reactome)
CANX:EBI3R-HSA-8950342 (Reactome)
CANX:EBI3R-HSA-8950362 (Reactome)
CANXArrowR-HSA-8950398 (Reactome)
CANXArrowR-HSA-8950740 (Reactome)
CANXR-HSA-8950387 (Reactome)
CRLF1:IL27ArrowR-HSA-8950504 (Reactome)
CRLF1:IL27ArrowR-HSA-8950731 (Reactome)
CRLF1:IL27R-HSA-8950731 (Reactome)
CRLF1R-HSA-8950504 (Reactome)
EBI3 geneR-HSA-8984963 (Reactome)
EBI3ArrowR-HSA-8984963 (Reactome)
EBI3R-HSA-8950387 (Reactome)
IL-35:(IL6ST:JAK1:JAK2) dimerArrowR-HSA-8983518 (Reactome)
IL-35:(IL6ST:JAK1:JAK2) dimerR-HSA-8983834 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer: STAT1ArrowR-HSA-8983841 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer: STAT1R-HSA-8983835 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer:p-STAT1ArrowR-HSA-8983835 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimer:p-STAT1R-HSA-8983845 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimerArrowR-HSA-8983845 (Reactome)
IL-35:(IL6ST:p-JAK1:p-JAK2) dimerR-HSA-8983841 (Reactome)
IL-35:IL27RA:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT3ArrowR-HSA-8984014 (Reactome)
IL-35:IL27RA:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT3R-HSA-8984023 (Reactome)
IL12A geneR-HSA-8984964 (Reactome)
IL12A:EBI3ArrowR-HSA-8950740 (Reactome)
IL12A:EBI3R-HSA-448627 (Reactome)
IL12A:IL12B:IL12RB1:p-Y-TYK2:IL12RB2:p-JAK2ArrowR-HSA-8950423 (Reactome)
IL12A:IL12B:IL12RB1:p-Y-TYK2:IL12RB2:p-JAK2R-HSA-8950757 (Reactome)
IL12A:IL12B:IL12RB1:p-Y-TYK2:IL12RB2:p-JAK2mim-catalysisR-HSA-8950757 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2:2xSTAT4ArrowR-HSA-8950448 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2:2xSTAT4R-HSA-8950354 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2:2xSTAT4mim-catalysisR-HSA-8950354 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2ArrowR-HSA-8950757 (Reactome)
IL12A:IL12B:IL12RB1:p-Y800-IL12RB2:p-Y-TYK2:p-JAK2R-HSA-8950448 (Reactome)
IL12A:IL12BArrowR-HSA-8950113 (Reactome)
IL12A:IL12BArrowR-HSA-8950128 (Reactome)
IL12A:IL12BArrowR-HSA-8950347 (Reactome)
IL12A:IL12BArrowR-HSA-8950575 (Reactome)
IL12A:IL12BArrowR-HSA-8950752 (Reactome)
IL12A:IL12BR-HSA-447226 (Reactome)
IL12A:IL12BR-HSA-8950347 (Reactome)
IL12A:IL12BR-HSA-8950575 (Reactome)
IL12A:IL12BR-HSA-8950752 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2ArrowR-HSA-447226 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2ArrowR-HSA-8981093 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2R-HSA-8950128 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2R-HSA-8950423 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2R-HSA-8981093 (Reactome)
IL12A:IL12RB1:TYK2:IL12B:IL12RB2:JAK2mim-catalysisR-HSA-8950423 (Reactome)
IL12AArrowR-HSA-8984964 (Reactome)
IL12AR-HSA-8950113 (Reactome)
IL12AR-HSA-8950362 (Reactome)
IL12B:IL23AArrowR-HSA-8950183 (Reactome)
IL12B:IL23AArrowR-HSA-8950741 (Reactome)
IL12B:IL23AR-HSA-447130 (Reactome)
IL12B:IL23AR-HSA-8950741 (Reactome)
IL12BArrowR-HSA-8950179 (Reactome)
IL12BR-HSA-8950113 (Reactome)
IL12BR-HSA-8950179 (Reactome)
IL12BR-HSA-8950183 (Reactome)
IL12BR-HSA-8950456 (Reactome)
IL12BTBarR-HSA-447226 (Reactome)
IL12RB1:TYK2:IL12RB2:JAK2ArrowR-HSA-447252 (Reactome)
IL12RB1:TYK2:IL12RB2:JAK2ArrowR-HSA-8950128 (Reactome)
IL12RB1:TYK2:IL12RB2:JAK2R-HSA-447226 (Reactome)
IL12RB1:TYK2ArrowR-HSA-8950057 (Reactome)
IL12RB1:TYK2R-HSA-447130 (Reactome)
IL12RB1:TYK2R-HSA-447252 (Reactome)
IL12RB1R-HSA-8950057 (Reactome)
IL12RB2:JAK2ArrowR-HSA-8950063 (Reactome)
IL12RB2:JAK2R-HSA-447252 (Reactome)
IL12RB2:JAK2R-HSA-6809140 (Reactome)
IL12RB2:JAK2R-HSA-8983519 (Reactome)
IL12RB2:JAK2R-HSA-8984001 (Reactome)
IL12RB2R-HSA-8950063 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:IL23R:p-JAK2ArrowR-HSA-8950591 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:IL23R:p-JAK2R-HSA-8950364 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:IL23R:p-JAK2mim-catalysisR-HSA-8950364 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3:STAT4ArrowR-HSA-8952749 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3:STAT4R-HSA-8950269 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3:STAT4mim-catalysisR-HSA-8950269 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3ArrowR-HSA-8950583 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:STAT3R-HSA-8952749 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:p-Y705-STAT3:p-Y693-STAT4ArrowR-HSA-8950269 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2:p-Y705-STAT3:p-Y693-STAT4R-HSA-8952823 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2ArrowR-HSA-8950364 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2ArrowR-HSA-8952823 (Reactome)
IL23A:IL12B:IL12RB1:p-TYK2:p-Y-IL23R:p-JAK2R-HSA-8950583 (Reactome)
IL23A:IL12B:IL23R:JAK2:IL12RB1:TYK2ArrowR-HSA-447130 (Reactome)
IL23A:IL12B:IL23R:JAK2:IL12RB1:TYK2R-HSA-8950591 (Reactome)
IL23A:IL12B:IL23R:JAK2:IL12RB1:TYK2mim-catalysisR-HSA-8950591 (Reactome)
IL23AR-HSA-8950183 (Reactome)
IL23R:JAK2ArrowR-HSA-8950737 (Reactome)
IL23R:JAK2R-HSA-447130 (Reactome)
IL23RR-HSA-8950737 (Reactome)
IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)ArrowR-HSA-448427 (Reactome)
IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)R-HSA-8950210 (Reactome)
IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)R-HSA-8950537 (Reactome)
IL27:EBI3:IL27RA:JAK1:IL6ST:JAK1,JAK2,(TYK2)mim-catalysisR-HSA-8950537 (Reactome)
IL27:EBI3:IL27RA:p-JAK1:IL6ST:p-JAK1,p-JAK2,p-TYK2ArrowR-HSA-8950537 (Reactome)
IL27:EBI3:IL27RA:p-JAK1:IL6ST:p-JAK1,p-JAK2,p-TYK2R-HSA-8950340 (Reactome)
IL27:EBI3:IL27RA:p-JAK1:IL6ST:p-JAK1,p-JAK2,p-TYK2mim-catalysisR-HSA-8950340 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2ArrowR-HSA-8950340 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2R-HSA-8950518 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3ArrowR-HSA-8950441 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3ArrowR-HSA-8950518 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3R-HSA-8950485 (Reactome)
IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-Y-TYK2:STAT1:STAT3mim-catalysisR-HSA-8950485 (Reactome)
IL27:EBI3ArrowR-HSA-448421 (Reactome)
IL27:EBI3ArrowR-HSA-8950210 (Reactome)
IL27:EBI3ArrowR-HSA-8950398 (Reactome)
IL27:EBI3R-HSA-448421 (Reactome)
IL27:EBI3R-HSA-448427 (Reactome)
IL27ArrowR-HSA-8950674 (Reactome)
IL27R-HSA-8950342 (Reactome)
IL27R-HSA-8950504 (Reactome)
IL27R-HSA-8950674 (Reactome)
IL27RA:JAK1ArrowR-HSA-8950210 (Reactome)
IL27RA:JAK1ArrowR-HSA-8950716 (Reactome)
IL27RA:JAK1R-HSA-448427 (Reactome)
IL27RA:JAK1R-HSA-8984001 (Reactome)
IL27RAR-HSA-8950716 (Reactome)
IL27RAR-HSA-8950766 (Reactome)
IL27TBarR-HSA-8950210 (Reactome)
IL35:(IL12RB2:JAK2 dimer)ArrowR-HSA-8983519 (Reactome)
IL35:(IL12RB2:JAK2 dimer)R-HSA-8983870 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:STAT4ArrowR-HSA-8983876 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:STAT4R-HSA-8983872 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:STAT4mim-catalysisR-HSA-8983872 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:p-STAT4ArrowR-HSA-8983872 (Reactome)
IL35:(IL12RB2:p-JAK2) dimer:p-STAT4R-HSA-8983878 (Reactome)
IL35:(IL12RB2:p-JAK2) dimerArrowR-HSA-8983870 (Reactome)
IL35:(IL12RB2:p-JAK2) dimerArrowR-HSA-8983878 (Reactome)
IL35:(IL12RB2:p-JAK2) dimerR-HSA-8983876 (Reactome)
IL35:(IL6ST:p-JAK1:p-JAK2:p-TYK2) dimerArrowR-HSA-8983834 (Reactome)
IL35:IL27RA:JAK1:IL12RB2:JAK2ArrowR-HSA-8984001 (Reactome)
IL35:IL27RA:JAK1:IL12RB2:JAK2R-HSA-8984012 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT3ArrowR-HSA-8984021 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT3R-HSA-8984014 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2ArrowR-HSA-8984012 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2ArrowR-HSA-8984023 (Reactome)
IL35:IL27RA:p-JAK1:IL12RB2:p-JAK2R-HSA-8984021 (Reactome)
IL35:IL6ST:JAK1:IL12RB2:JAK2ArrowR-HSA-6809140 (Reactome)
IL35:IL6ST:JAK1:IL12RB2:JAK2R-HSA-8950405 (Reactome)
IL35:IL6ST:JAK1:IL12RB2:JAK2mim-catalysisR-HSA-8950405 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT4ArrowR-HSA-8983996 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT4R-HSA-8950453 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:STAT1:STAT4mim-catalysisR-HSA-8950453 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT4ArrowR-HSA-8950453 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2:p-STAT1:p-STAT4R-HSA-8983983 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2ArrowR-HSA-8950405 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2ArrowR-HSA-8983983 (Reactome)
IL35:IL6ST:p-JAK1:IL12RB2:p-JAK2R-HSA-8983996 (Reactome)
IL35ArrowR-HSA-448627 (Reactome)
IL35R-HSA-6809140 (Reactome)
IL35R-HSA-8983518 (Reactome)
IL35R-HSA-8983519 (Reactome)
IL35R-HSA-8984001 (Reactome)
IL6ST:JAK1, JAK2, (TYK2)ArrowR-HSA-1067646 (Reactome)
IL6ST:JAK1, JAK2, (TYK2)ArrowR-HSA-8950210 (Reactome)
IL6ST:JAK1, JAK2, (TYK2)R-HSA-448427 (Reactome)
IL6ST:JAK1, JAK2, (TYK2)R-HSA-6809140 (Reactome)
IL6ST:JAK1, JAK2, (TYK2)R-HSA-8983518 (Reactome)
IL6STR-HSA-1067646 (Reactome)
JAK1, JAK2, (TYK2)R-HSA-1067646 (Reactome)
JAK1R-HSA-8950716 (Reactome)
JAK2R-HSA-8950063 (Reactome)
JAK2R-HSA-8950737 (Reactome)
P4HBmim-catalysisR-HSA-8950113 (Reactome)
P4HBmim-catalysisR-HSA-8950183 (Reactome)
P4HBmim-catalysisR-HSA-8950456 (Reactome)
R-HSA-1067646 (Reactome) The tyrosine kinases JAK1, JAK2 and Tyk2 associate with the cytoplasmic domain of the interleukin-6 receptor beta subunit (IL6ST, GP130) (Stahl et al. 1994), via interactions with the membrane proximal Box1/Box2 region, motifs conserved amongst many cytokine receptors. This region of IL6ST is sufficient for JAK activation (Narazaki et al. 1994). The interbox region is also involved in JAK binding (Haan et al. 2000). This is a strong and stable assocation considered to be constitutive (Heinrich et al. 2003). The N-terminal region of JAK1 contains a FERM domain that is crucial for receptor association (Haan et al. 2001, Hilkens et al. 2001). Interleukin-6 (IL6) induces rapid phosphorylation and activation of JAK1, JAK2 and TYK2 in cells (Guschin et al. 1995), but experiments in JAK1 deficient cell lines (Guschin et al. 1995) and Jak1 -/- mice (Rodig et al. 1998) where IL6-induced responses (Il6st phosphorylation and actvation of Stat1 and Stat3) were greatly impaired, suggest that JAK1 is the key kinase for signal transduction. One possible model is that JAK1 associates with IL6ST and triggers downstream events, but requires either JAK2 or TYK2 for efficient activation or ligand-induced dimerization of the receptor complex.
R-HSA-447130 (Reactome) Interleukin-23 (IL23) is a complex of Interleukin-23 subunit alpha (IL23A) and Interleukin-12 subunit beta (IL12B, IL-12p40). IL12B is also a component of Interleukin-12 (IL12) (Oppmann et al. 2000, Lupardus & Garcia et al. 2008).
The Interleukin-23 receptor consists of Interleukin 23 receptor subunit (IL23R) and Interleukin 12 receptor subunit beta 1 (IL12RB1). IL12RB1 is shared with the Interleukin-12 receptor.
The Interleukin-23 receptor binds IL23 but does not interact with IL12. IL12RB1 is required to confer IL23 responsiveness in cells (Parham et al. 2002).
IL23 is produced by antigen presenting cells and promotes the expansion and survival of a distinct lineage of T cells called T helper 17 (Th17) (Langrish et al. 2005). Increasing evidence supports the idea that Th17 cells do not require traditional T helper 1(Th1) or T helper 2 (Th2) transcription factors or regulatory genes, and that their differentiation is inhibited by Interferon-gamma (IFNG) and Interleukin 4 (IL4) (Hoeve et al. 2006).
Naive T cells cultured in the presence of Transforming growth factor beta 1(TGFB1) and Interleukin 6 (IL6) and in the absence of IFNG or IL4 are polarized to Th17 cells and upregulate IL23R (Veldhoen et al. 2006).

Subsequently, IL23 appears to be required for the expansion and survival of Th17 cells. Like Th1 and Th2 cells, Th17 cells remain committed to their lineage, even in the presence of other Th polarizing cytokines (Harrington et al. 2005).
The Interleukin 23 receptor ligand interaction has been shown to activate Signal transducer and activator of transcription 3 (STAT3), resulting in binding to the Interleukin 17A(IL17A) and Interleukin 17F (IL17F) promoters. The T cell response activated by Interleukin 23 heterodimer is attenuated by Suppressor of cytokine signaling 3 (SOCS3), which acts as a feedback inhibitor to regulate Th17 cells (Chen et al. 2006).

Knockout mice deficient in either IL12B or IL23A, or in either subunit of the Interleukin-23 receptor (IL23R or IL12RB1) have reduced symptoms of multiple sclerosis and inflammatory bowel disease suggesting that IL23 is involved in these inflammatory diseases (Kikly et al. 2006).
As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as a black box event.
R-HSA-447226 (Reactome) Interleukin-12 (IL12) is a heterodimer of interleukin 12 alpha subunit (IL12A, IL-12p35) and interleukin 12 beta subunit (IL12B, IL-12p40) that binds the Interleukin 12 receptor, which is a heterodimer of Interleukin 12 receptor alpha subunit (IL12RB1) and Interleukin 12 beta subunit (IL12RB2) (Chua et al. 1994, Yoon et al. 2000, Chizzonite et al. 1992 , Gubler et al. 1991). The data from cross linking and surface labeling experiments suggest that only heterodimeric receptors bind IL12.
Dimerization of the receptor does not depend on IL12 binding to the receptor subunits but if the IL12 is pre-bound to either receptor subunit, the resulting binding pattern does not change (Chua et al. 1994).

Regulation:
IL12B monomer can be secreted and interact with the Interleukin 12 receptor. Human IL12B homodimers can be produced by cells containing expression constructs (Ling et al. 1995, Alloza & Vandenbroeck 2015) but not under natural conditions (Carra et al. 2000). IL12B homodimers do not mediate biological activity, rather they act as a competitive antagonist by competition with IL12 (Ling et al. 1995).
R-HSA-447252 (Reactome) Interleukin-12 receptor beta 2 (IL12RB2) is a type I transmembrane protein with a 595-amino-acid-long extracellular domain and a cytoplasmic tail of 216 amino acids that contains three tyrosine residues. It binds Interleukin-12 with low affinity. IL12RB2 binds Interleukin 12 receptor beta 1 subunit (IL12RB1) forming the high affinity Interleukin-12 receptor (Presky et al. 1996a, 1996b), which signals via JAK2 and TYK2 (Zou et al. 1997).
R-HSA-448421 (Reactome) When Interleukin-27 subunit beta (EBI3) was expressed in cells, it accumulated in the endoplasmic reticulum and associated with the molecular chaperone calnexin(CANX), indicating that subsequent processing and secretion might be dependent on association with a second subunit (Devergne et al.1996)
Interleukin-27 subunit alpha (IL27) coexpressed with EBI3 permitted secretion as a soluble complex (Pflanz et al. 2002)

This is a black box event because there is not reported evidene about the mechanism of the traslocation of the IL-27 heterodimer from the endoplasmic reticulum to the extracellular region.
R-HSA-448427 (Reactome) Interleukin-27 is a heterodimer composed of Interleukin-27 subunit alpha (IL27) and Epstein-Barr virus-induced gene 3 (EBI3). It binds to the Interleukin-27 heterodimeric receptor, which is composed of Interleukin-27 receptor subunit alpha (IL27RA, WSX-1) and Interleukin-6 receptor subunit beta (IL6ST, gp130). IL6ST is a signal transducing protein that is a component of several other cytokine receptors including the Interleukin-6 and Interleukin-11 receptors (Pflanz et al. 2004). In the absence of IL27RA, Interleukin-27 can bind to IL6ST but with low affinity (Jia et al. 2016).
Regulation: IL27RA can be cleaved releasing a soluble form (sIL27RA) that can bind to Interleukin-27 and antagonize Interleukin-27 binding to its heterodimer receptor (Dietrich et al. 2014).
R-HSA-448627 (Reactome) Interleukin-35 heterodimer is formed by interleukin-12 alpha (IL12A or IL12p35) and Interleukin 27 subunit beta (EBI3).
EBI3 monomer can be found at the endoplasmic reticulum and is not secreted since it remains associated to the protein calnexin (CANX). So is suggested EBI3 needs the association with another subunit to be released to the extracellular region (Devergne et al. 1996).
Interleukin-35 affects and is specifically produced by regulatory T cells and regulatory B cells (Niedbala et al. 2007, Wang et al. 2014, Egwuagu et al. 2015, Fonseca-Camarillo et al. 2015). This interleukin is secreted and inhibits T cell proliferation (Collison et al. 2007).
This reaction is a black box event because we know the Interleukin-35 heterodimeric protein is secreted but there is no reported evidence from which compartment and which mechanism is involved in the traslocation.
R-HSA-6809140 (Reactome) Interleukin-35 (IL35) is a heteromeric complex of Interleukin-12 subunit alpha (IL12A) and Interleukin-27 subunit beta (EBI3, IL27B) ) induces hetero and homodimers of Interleukin 6 receptor beta precursor (IL6ST, gp130) and Interleukin 12 receptor beta 2 (IL12RB2).

These results suggested that Interleukin 35 is bound to these three receptor subunits providing insight into the partial resistance to Interleukin 35 mediated suppression observed after the deletion of a single chain. Moreover there is the possibility of the assembly of higher structures by Interleukin 35, as has been suggested for Interleukin 6 receptor subunit beta precursor. IL12RB2 and IL6ST represent the most plausible components of Interleukin 35 receptor. However, additional molecules might facilitate cytokine binding or downstream signaling, although this would be unprecedented in the Interleukin 6 receptor and Interleukin 12 receptor families (Collison et al. 2012)

Moreover Interleukin 35 (IL35) uses an unique heterodimer of receptor chains Interleukin 12 receptor subunit beta (IL 12RB2) and Interleukin 6 receptor subunit beta (gp130 or IL6ST) for its signal transduction. The composition of Interleukin 35 heterodimeric receptor is not totally elucidated, but Interleukin 35–Interleukin 35 receptor interaction and assembly given the `site 1 2 3' follows an architectural paradigm originally established for Interleukin 6 (IL 6) (Boulanger et al. 2003).

Computational analysis suggests 3 potential conformations of Interleukin 35/Interleukin 35 Receptor complex: First, IL6ST binds to site 2 in the Interleukin 6(IL 6), Ciliary neurotrophic factor (CNTF) and LIF (Leukemia inhibitory factor) complexes and thus could do so in the IL 35 IL35R complex, leaving IL12RB2 to bind site 3. Second, the Interleukin 35–Interleukin 35 receptor complex could form symmetric homohexameric assemblies (2:2:2) analogous to the Interleukin 6 receptor complex, thus allowing IL 12RB2 and IL6ST to each bind to site 3 on IL12A. Third, IL6ST and IL12RB2 could both be capable of binding to site 2 and site 3 and therefore exist in an interchanging equilibrium of heterotetrameric complexes (at a ratio of 1:1:1:1, IL6ST to IL12RB2 to Interleukin 27 beta subunit (EBI3). Indeed, studies of the Interleukin 6 ligand receptor complex suggest that it may be able to signal as tetrameric or hexameric assembly.

Finally, a previously unknown mode of binding may exist that uses the site 1 2 3 model in a manner not predicted on the basis of the existing structural information for IL 6, LIF and CNTF (Collison et al. 2012).

As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as a black box event.
R-HSA-8950057 (Reactome) The intracellular domain of human Interleukin-12 receptor subunit beta-1 (IL12RB1) but not the intracellular domain of Interleukin-12 receptor subunit beta-2 (IL12RB2) interacts directly with Non-receptor tyrosine-protein kinase (TYK2) (Zou et al. 1997)
Inferred from mouse:
TYK2 associates with IL12RB1. In the absence of TYK2, IL12RB1 can associate with Tyrosine-protein kinase JAK1 (JAK1) (Floss et al. 2016).
R-HSA-8950063 (Reactome) Inferred from human protein interaction:
Tyrosine-protein kinase JAK2 (JAK2) can associates with the intacellular domain of Interleukin-12 recetor subunit beta 2 (IL12RB2). Interleukin-12 receptor subunit beta 1 (IL12RB1) and Non-receptor tyrosine-protein kinase TYK2 (TYK2) are not required (Zou et al.1997, Floss et al. 2016 ,Yamamoto et al. 1999).
R-HSA-8950113 (Reactome) The Interleukin-12 heterodimer (IL-12) is formed by Interleukin-12 subunit alpha (IL12A, IL-12p35) and Interleukin-12 subunit beta (IL12B, IL-12p40) (Podlaski et al. 1992, Kobayashi et al. 1989, Stern et al.1990). Heterodimerization occurs due to charged residue interactions (Yoon et al. 2000) and is stabilized by disulfide bounding.
IL12 heterodimerization is believed to occur in the endoplasmic reticulum (ER) because inhibition of the enzyme Prolyl 4-hydroxylase subunit beta (P4HB), referred to in this article as Protein disulfide isomerase (PDI), by bacitracin causes IL-12 retention in the ER (Alloza & Vandenbroek 2005).
R-HSA-8950128 (Reactome) Based on competition experiments with Iodine125-labeled Interleukin-12 (IL12) it was determined that IL12 can dissociate from the Interleukin-12 receptor. The association kinetics suggest mostly subsequent internalization of the IL12 (Chizzonite et al. 1992).
R-HSA-8950179 (Reactome) Interleukin-12 subunit beta (IL12B, IL12p40) is secreted to the extracellular region.
Celecoxib and the 4-trifluoromethyl analogue of celecoxib (TFM-C) inhibit secretion of Interleukin-23, a dimer of Interleukin-23 subunit alpha (IL23A) and IL12B but do not affect the secretion of monomeric IL12B (McLaughlin et al. 2010).

This is a Black box event because the mechanism of IL12B secretion is unknown.
R-HSA-8950181 (Reactome) Once activated by tyrosine phosphorylation, Signal transducer and activator of transcription 4 (STAT4) forms a homodimer, translocates to the nucleus, binds to specific DNA sequences representing an IFN-gamma response element (also known as gamma-interferon-activation sites (GAS)) (Bacon et al. 1995). Using electrophoretic mobility shift assay (EMSA), confocal laser microscopy and Western blotting, nuclear translocation of STAT4 in response to Interleukin-12 (IL12) has been demonstrated in Phytohaemagglutinin (PHA) activated T cells (Toyoda et al. 2004). Using confocal laser microscopy, nuclear translocation of STAT4 in response to IL12 has also been demonstrated in B cells(Durali et al. 2003)

Translocation to the nucleus is presented as a black box event because the exact mechanism of translocation is unknown.
R-HSA-8950183 (Reactome) Interleukin 23 subunit alpha (IL23A, IL23-p19) and Interleukin 12 subunit beta (IL12B, IL-12p40) bind to form the Interleukin-23 (IL23) heterodimeric complex (IL23A:IL12B). When 293T cells were transfected with IL23A only a small amount of protein could be immunoprecipitated from the supernatant, while protein was readily detected in cellular lysates, indicating inefficient secretion. Co expression of IL23A with IL12B enhanced secretion of IL23 (Oppmann et al. 2000). Moreover there is a disulfide bridge within IL12A which is necessary fro IL12B-induced secretion. Protein disulfide isomerases enable the formation of these bridges (Reitberger et al. 2017).
R-HSA-8950210 (Reactome) Interleukin-27 heterodimer (IL27) binds a heterodimeric receptor formed by Interleukin-27 subunit alpha (IL27RA) and Interleukin-6 receptor subunit beta (IL6ST, gp130). In the absence of IL27RA IL27 can bind IL6ST with low affinity. Dissociation rate constants for binding of IL27 to the heterodimeric receptor indicate a slow dissociation rate, resulting in very high binding affinity. Blocking both receptor chains completely blocks IL27 induced STAT1 and STAT3 phosphorylation and IL27 induced proliferation (Jia et al. 2016).
R-HSA-8950269 (Reactome) Interleukin-23 (IL23) induces Signal transducer and activator of transcription 3 (STAT3) and STAT4 phosphorylation. Non-receptor tyrosine-protein kinase TYK2 (TYK2) and Tyrosine-protein kinase JAK2 (JAK2) are believed to phosphorylate STAT3 and STAT4 (Parham et al. 2002). STAT3 is the most prominent STAT activated by IL23, contrasting with Interleukin-12 (IL12) which predominantly induces STAT4 activation (Parham et al. 2002). IL23 induces phosphorylation of STAT3 and STAT4 in NK-like T cells but neither in NK cells (van de Wetering et al. 2009). Phosphorylation results in STAT3:STAT4 heterodimer formation (Parham et al. 2002).
This is a black box event because the exact mechanism and order of STAT3/STAT4 binding is unknown.
R-HSA-8950271 (Reactome) Inferred from mouse:
Mouse Soluble isoform of Interleukin-27 receptor alpha subunit (sIl27ra or WSX-1) can be produced by two mechanisms. There is experimental evidence of expression of sIl27ra in primary cortical neurons (PCNs) (Hashimoto et al. 2010). Human sIL27RA is produced by activated CD4(+) and CD8(+) T cells, B cells, myeloid cells and various cell lines.

sIL27RA is released as two N-glycosylated variants of around 90 and 70 kDa. Production is inhibited by the metalloprotease inhibitors GM6001 (galardin, ilomastat) and Tumor necrosis factor-alpha processing inhibitor-0 (TAPI-0). sIL27RA is a natural antagonist of Interleukin-27 (Dietrich et al. 2014)
As the origin of sIL27RA is unclear this is a black box event.
R-HSA-8950340 (Reactome) Interleukin-27 receptor is formed by Interleukin-27 receptor subunit alpha (IL27RA, WSX-1) and Interleukin-27 receptor subunit beta (IL6ST, gp130). Both subunits can be tyrosine phosphorylated after ligand-receptor interaction (Pflanz et al. 2004, Takeda et al. 2003). There is general agreement that ligand binding to cytokine receptors results in the activation of prebound Jak kinases, which auto- and transphosphorylate then phosphorylate key tyrosine residues on the receptor (O'Shea et al 2002), but for the interleukin-27 receptor the pattern of phosphorylations is not clear, hence this is represented as a black box event.
R-HSA-8950342 (Reactome) Interleukin 27 subunit alpha (IL27, IL-27p28) binds Interleukin 27 subunit beta (EBI3) forming the Interleukin 27 heterodimeric complex (IL27:EBI3). When expressed alone, human EBI3 is associated with the endoplasmic reticulum (ER) resident molecular chaperone calnexin (CANX) and is retained in the ER (Devergne et al 1996). Co expression of IL27 and EBI3 enables formation of IL27:EBI3, allowing secretion (Pflanz et al. 2002).

This is a Black Box event because there is not reported which reaction occurs first: the association of IL27 to EBI3:CANX and later the Interleukin 27 heterodimeric protein formation or first the dissociation of EBI3 from CANX and later formation of the Interleukin 27 heterodimeric protein formation. Since the EBI3 is retained in the endoplasmic reticulum as a complex with CANX (Devergne et al. 1996), and the co expression of IL27 and EBI3 enable the formation of the Interleukin 27 heterodimeric complex formation, allowing secretion of this protein (Pflanz et al. 2002).

R-HSA-8950347 (Reactome) Vesicle-associated membrane protein 7 (VAMP7) plays a dual role in Interleukin-12 heterodimeric protein secretion. In individual Dendritic cells, its basic function is as a positive regulator, regulating the optimal exocytosis of biologically active Interleukin-12 heterodimer produced by inflammatory stimuli. The second essential role of VAMP7 is as a negative regulator, controling non-redundantly synaptic secretion of the cytokine during interaction with a cognate T cell, i.e., at the immune synapse. Multivesicular bodies are regulated by VAMP7 and consequently Interleukin-12 heterodimer secretion is regulated by this VAMP7 (Chiaruttini et al. 2016).
R-HSA-8950354 (Reactome) Inferred from mouse:
Signal transducer and activator of transcription 4 (STAT4) is activated via interaction with tyrosine-800 of Interleukin-12 receptor beta 2 subunit (IL12RB2). Based on experiments with murine-specific peptides, STAT4 activation depends on interaction with the peptide sequence pYLPSNID, where pY represents phosphotyrosine. STAT1 and STAT3 are not activated directly through the Interleukin-12 heterodimeric receptor (Naeger et al. 1999).
As the pattern of phosphorylations required for this event is unclear, it is represented here as a black box event.
R-HSA-8950362 (Reactome) Interleukin-35 is a heterodimer of Interleukin-27 subunit beta (EBI3) and Interleukin-12 subunit alpha (IL12A or IL12-p35) (Devergne et al. 1997). It is required for maximal T regulatory cell activity (Collison et al. 2007).
Site directed mutagenesis of IL12A identified mutations that disrupt formation of Interleukin 12 and Interleukin 27 heterodimeric complexes but not Interleukin 35. IL12A appears to pair with EBI3 entirely differently from IL27. (Jones et al. 2012). In the absence of IL12A, EBI3 is retained in the endoplasmic reticulum, associated with the chaperone Calnexin (CANX) (Devergne et al. 1997).
This is a Black Box event because we know that EBI3 is retained as a complex with CANX and the co expression of EBI3 and IL12A enables their secretion, but we don't have evidence about the mechanism of dissociation of CANX from EBI3 (Devergne et al. 1997).


R-HSA-8950364 (Reactome) Inferred from mouse:
Interleukin-23 receptor subunit (Il23r) can be phosphoryated at various intracellular Tyrosin residues. Tyr-542 and Tyr-626 aminoacid residues in murine Il23r are responsible for SH2 domain dependent Signal transducer and activator of transcription 3 (Stat3) activation (Floss et al. 2013). Moreover Western blot data demostrated Interleukin-23 dependent trysoine phosphorylation of Stat3 in cotransfected parental cell lines(2C4, 2fTGH) and Tyrosine-protein kinase JAK1(Jak1)-deficient cells (U4C) (Floss et al.2016).
As the process of phosphorylation is not clear this reaction is represented here as a black box event.
R-HSA-8950387 (Reactome) Calnexin (CANX or p95 calnexin) binds Interleukin-27 subunit beta (EBI3, IL27B). In human cell lines (BL30, BL41, Louckes, BJAB, P3HR1) most newly synthesized EBI3 is retained in the endoplasmic reticulum (ER) in an endoglycosidase H-sensitive form (Devergne et al. 1996, 1997), bound to CANX and a 60-kDa protein and transiently with a p75-kDa protein, both ignored here). EBI3 can be released by itself but the association with CANX prevents this, the complex is retained in the ER. The co-expression of other interleukin subunits enables the release of EBI3 in a complex with Interleukin-27 subunit alpha (IL27) (Devergne et al. 1996).
R-HSA-8950398 (Reactome) Interleukin 27 subunit alpha (IL27, IL-27p28) binds Interleukin 27 subunit beta (EBI3) forming the Interleukin 27 heterodimeric complex (IL27:EBI3). When expressed alone, human EBI3 is associated with the endoplasmic reticulum (ER) resident molecular chaperone calnexin (CANX) and is retained in the ER (Devergne et al. 1997). Co expression of IL27 and EBI3 enables formation of IL27:EBI3, allowing secretion (Pflanz et al. 2002).
This is a Black Box event because there is not reported which reaction occurs first: the association of IL27 to EBI3:CANX and later the Interleukin 27 heterodimeric protein formation or first the dissociation of EBI3 from CANX and later formation of the Interleukin 27 heterodimeric protein formation.
R-HSA-8950405 (Reactome) Interleukin 35 (IL35) may presumably signal via a complex that includes Tyrosine protein kinase JAK1 (JAK1) and JAK2 associated with Interleukin 6 receptor beta subunit (IL6ST) and Interleukin 12 receptor beta 2 subunit (IL12RB2) (Collison et al. 2012). These JAKs are believed to phosphorylate Signal transducer and activator of transcription 1 (STAT) (Stark GR and Darnell JE, 2012). As the series of events that induces JAK/STAT phosphorylation events in response to IL35 are not clear, this event is represented as a black box.
R-HSA-8950410 (Reactome) Interleukin-12 subunit beta (IL12B, IL-12p40) can form oligomers with other interleukin subunits or be secreted as a monomer to the extracellular region (Ling et al. 1995).
Production of human IL12B homodimers has only been detected in cells with IL-12p40 expression constructs (Ling et al 1995, Alloza & Vandenbroeck 2015), not in natural conditions (Carra et al 2000).
R-HSA-8950423 (Reactome) Interleukin-12 phosphorylates and thereby activates Tyrosine-protein kinase JAK2 (JAK2) and non-receptor tyrosine-protein kinase TYK2 (TYK2) (Bacon et al.1995, Kanda & Watanabe 2008).
R-HSA-8950441 (Reactome) Signal transducer and activator of transcription 1-alpha/beta (STAT1) and Signal transducer and activator of transcription 3 (STAT3) dissociate from the receptor complex after activation.
This is a BlackBox event since the exact mechanism of this dissociation is unknown.
R-HSA-8950448 (Reactome) Signal transducer and activator of transcription 4 (STAT4) binds to phosphorylated tyrosine-800 and a few surronding amino acids on Interleukin-12 receptor subunit beta 2 (IL12RB2) (Yao et al. 1999).
R-HSA-8950453 (Reactome) Interleukin-35 (IL35) binding activates the IL35 receptor complex and facilitates Tyrosine-protein kinase JAK (JAK) phosphorylation. Subsequently, Signal transducer and activator of transcription 1-alpha/beta (STAT1) and STAT4 bind to the receptor complex and are activated by tyrosine phosphorylation (Collison et al. 2012). Although it is known that JAKs are involved in STATs phosphorylation (Stark GR and Darnell JE, 2012), it is not clear how other components of the IL35 receptor complex contribute to STAT1/STAT4 phosphorylation. For this reason, this event is assigned a black box status.
R-HSA-8950456 (Reactome) Murine cells have been shown to produce Interleukin-12 homodimer (IL-12p80) (Gillessen et al. 1995). In a cell-free system porcine Interleukin 12 homodimer (IL-12p80) is formed from two subunits of Interleukin 12 subunit beta (IL12B, IL-12p40), stabilized by a disulfide link. The cysteine in position 197 of IL12B is required for homodimer formation. Prolyl 4-hydroxylase subunit beta (P4HB), in this article referred to as protein disulfide isomerase (PDI), can act as a chaperone to induce homodimer formation (Martens et al. 2000). Human cells do not produce IL-12p80 under normal conditions (Ling et al. 1995), when however expressed acts as an antagonist of Interleukin-12 signaling, competing with the Interleukin 12 heterodimer (IL12) for its receptor (Ling et al. 1995).
R-HSA-8950485 (Reactome) Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 1 alpha/beta (STAT1) are phosphorylated after Interleukin-27 (IL27) binds the Interleukin-27 receptor. In Interleukin-2 activated T cells, Interleukin-6 receptor beta subunit (IL6ST, gp130) has STAT3-docking sites, the result of tyrosine phosphorylation by Tyrosine protein-kinase JAK2 (JAK2) and/or Non receptor Tyrosine-protein kinase 2 (TYK2) and JAK1.

In human keratynocytes, Interleukin-12 (IL12) enhanced tyrosine phosphorylation and transcriptional activity of STAT3, possibly mediated by JAK2, which is associated with Interleukin-12 receptor beta 2 subunit (IL12RB2). However Interleukin-23 (IL23) and IL27 did not activate STAT3 in keratinocytes although JAK2 was activated (Kanda & Watanabe 2008)

Inferred from mouse:
As further background, the heterodimeric proteins IL12, IL23 and IL27 activate JAK2 and Non-receptor tyrosine-protein kinase TYK2 (TYK2). IL27 simultaneously activates JAK1. STAT3 is required for IL27 induced up-regulation of c-Myc and Pim-1 and consequent cell proliferation. IL27-induced STAT3 activation is mediated through four tyrosine residues in the YXXQ motif of the cytoplasmic region of IL6ST, as observed with IL6. On the other hand, STAT3 is dispensable for IL27-induced augmentation of Th1 differentiation and IL27 induced supression of proinflammatory cytokine production.
In human keratynocytes IL27 induced both tyrosine phosphorylation and the transcriptional activity of STAT1 in parallel with the activation of JAK1. In IL27-activated naive T cells, the cytoplasmic domain of interleukin-27 receptor alpha subunit (IL27RA, WSX-1) is tyrosine phosphorylated by constitutively associated JAK1, providing a docking site for STAT1 which leads to its phosphorylation and activation by JAK1 (Kanda & Watanabe 2008). Moreover STAT1 silencing in human monocytic THP-1 cells demostrated that IL27 strongly increases STAT1 protein expression. Concomitant with increased STAT1 expression, Interleukin-10 (IL10) induced increased levels of STAT1 tyrosine phosphorylation in monocytes. All of these observations are consistent with results obtained with STAT1-deficient mice, which indicate that STAT1 activation is important for IL27-induced cell proliferation (Owaki et al. 2008).

This is a black box event because the exact mechanism and order of STAT1 and STAT3 binding is unknown.
R-HSA-8950504 (Reactome) Interleukin 27 alpha subunit (IL27, IL 27p28) can bind Cytokine receptor like factor 1 (CRLF1). IL27 has greatest homology with Interleukin 11 (IL11) and CRLF1. The IL27:CRLF1 complex is produced in dendritic cells and stimulates Natural Killer (NK) cells, increasing Interleukin 12 and Interleukin 2 induced Interferon gamma (IFNG) production and activation of marker expression.

Experiments with Ba/F3 transfectants indicate that IL27:CRLF1 activates cells expressing Interleukin 6 receptor subunit alpha (IL6R) in addition to the Interleukin 27 receptor subunits WSX1 and gp130. When tested on CD4+ and CD8+ T cells, IL27:CRLF1 induces Interleukin 6 receptor subunit alpha (IL6RA) dependent Signal transducer and activator of transcription 1 alpha/beta (STAT1) and STAT3 phosphorylation (Crabé et al. 2009). This reaction is a Black Box event since we know this complex forms and is secreted but do not know the compartment where dimer formation takes place.

R-HSA-8950518 (Reactome) Signal transducer and activator of transcription 1 (STAT1) and STAT3 are both known to be phosphorylated by Interleukin-27 (IL27) in human cells (Hibbert et al 2003 ).
R-HSA-8950522 (Reactome) Interleukin-35 (IL-35) uses a unique Signal transducer and activator of transcription 1-alpha/beta - Signal transducer and activator of transcription 4 (STAT1:STAT4) heterodimer (Collinson et al. 2012) for signaling. Several cytokine receptors activate STAT1 and STAT4 to drive proinflammatory T helper 1 type responses, so it is unclear how their activation via the interleukin-35 receptor gives rise to a unique STAT dimer.
T cells stimulated with Interleukin-12 plus IFN-gamma (IFNG) induce minimal interaction of a STAT1:STAT4 with consensus STAT-binding sites in the IL12A and EBI3 promoters. However, T cells stimulated with Interleukin-35 showed considerable enrichment for the binding of STAT1 and STAT4 to IL12A position 250 and EBI3 position 500, as well as other sites in their promoters.
This reaction is presented as a black box because the exact mechanism of traslocation to the nucleus is unclear.
R-HSA-8950537 (Reactome) Interleukin 27 phosphorylates/activates Tyrosine protein kinase JAK2 (JAK2) , non receptor tyrosine protein kinase TYK2 (TYK2) and Tyrosine protein kinase JAK1 (JAK1) (Kanda & Watanabe 2008). JAK1 interacts with IL27RA (Takeda et al 2003 )
As the phosphorylation required for Interleukin 27 induced activation are not clear, this is represented here as a black box event.

R-HSA-8950575 (Reactome) Inferred from mouse :
Interleukin-12, (IL12) formed from Interleukin-12 subunit alpha (IL12A) and Interleukin-12 subunit beta (IL12B), has been localized intracellularly in late endocytic vesicles expresing the marker protein termed Vesicle-associated membrane protein 7 (VAMP7) (Chiaruttini et al. 2016).

This reaction is a black box event because we do not fully understand the mechanism of translocation.
R-HSA-8950583 (Reactome) Inferred from mouse :
Signal transducer and activator of transcription 3 (STAT3) binds tyrosine residues of the Interleukin-23 receptor (IL23R) after cytokine-receptor interaction (Dumoutier et al. 2009, Floss et al. 2013). This is a black box event because STAT3 binding as a consequence of Interleukin-23 stimulation has not been directly demonstrated. IL23R can also bind STAT4, this alternative binding is not represented here only because the evidence for STAT3 binding is inferred from mouse/human chimeras while STAT4 binding evidence was obtained with human protein data.
R-HSA-8950591 (Reactome) In human cells IL-23 binding leads to phosphorylation and activation of TYK2 and JAK2 (Parham et al 2002). Inferred from mouse:
The intracellular domain of Interleukin 12 receptor beta 1 subunit (Il12rb1), spanning amino acid residues 592–656, is crucial for Interleukin 23 complex–induced cellular proliferation and Signal transducer and activator of transcription 3 (Stat3) phosphorylation (Floss et al. 2016).
As it is not clear what induces JAK2 and TYK2 kinase phosphorylation this is represented here as a black box event.
R-HSA-8950674 (Reactome) Inferred from mouse:
Experiments in cells transfected with mouse Interleukin 27 subunit beta (Ebi3) and Interleukin 27 subunit alpha (Il27, IL27p28) showed that Il27 can be secreted as a monomer, whereas mouse Ebi3 protein is secreted only as heterodimers with Il27 (Shimozato et al. 2009). Il27, independently of Ebi3, can antagonize cytokine signaling through Interleukin 6 receptor subunit beta (Il6st, gp130) and Interleukin 6 (Il6) mediated production of Interleukin 17 (Il17) and Interleukin 10 (Il10) (Stumhofer et al. 2010).

This reaction is a black box event because the mechanism of Il27 translocation is unknown.

R-HSA-8950716 (Reactome) Inferred from mouse:
The cytoplasmic domain of Interleukin-27 receptor subunit alpha (Il27ra) has a Box-1 motif which is important for binding to the Janus kinase family of proteins (Sprecher et al. 1998). Mouse Interleukin-27 receptor alpha (Il27ra, WSX-1) has been shown to directly associate with Tyrosine-protein kinase JAK1 (Jak1) as well as Signal transducer and activator of transcription 1-alpha/beta (Stat1) . Coimmunoprecipitation studies and pull-down assays suggest that the Il27ra directly associates with Jak1 and that one of its tyrosine residues provides a docking site for Stat1 when phosphorylated (Takeda et al. 2003).
R-HSA-8950724 (Reactome) Interleukin-23 receptor signaling leads to Signal transducer and activator of transcription 3/Signal transducer and activator of transcription 4 (STAT3:STAT4) heterodimer activation in addition to the activation of STAT3 homodimers. Although Interleukin 23 activates the same spectrum of JAK/STAT molecules as interleukin 12, Interleukin-23 activates STAT4 to a lesser extent (Oppmann et al. 2000, Parham et al. 2012). The STAT3:STAT4 heterodimer translocates to the nucleus.
This reaction is presented as a black box event because the exact mechanism of translocation to the nucleus is unknown.
R-HSA-8950731 (Reactome) Interleukin 27 alpha subunit (IL27,IL27A, IL27p28) and Cytokine like factor 1 (CRLF1) form a secreted complex. Secretion of IL27 was observed in HEK 293 cells transfected with IL27 cDNA in the absence of CRLF1. This may indicate that formation of a complex is not strictly required for IL27 secretion in these cells. Alternatively it could reflect the formation of a complex between IL27 and endogenous CRLF1, which is expressed in HEK 293 cells. The IL27:CRLF1 complex is biologically active (Crabé et al. 2009).

This reaction is a black box event because the mechanism of translocation is unknown.
R-HSA-8950733 (Reactome) Experiments show the presence of nuclear phosphorylated Signal transducer and activator of transcription 1-alpha/beta:Signal transducer and activator of transcription 3 (STAT1:STAT3) heterodimers after activation by Interleukin-6 or Interleukin-27 (Guzzo et al. 2010, Hirahara et al. 2015).
This event is presented as a black box event because the exact mechanism of translocation is unknown.
R-HSA-8950737 (Reactome) Inferred from mouse:

Interleukin-23 heterodimeric receptor, formed by Interleukin-23 receptor (Il23r) and Interleukin-12 receptor beta 1 subunit (Il12rb1), can bind Tyrosine-protein kinase JAK2 (Jak2). This association is essential for Interleukin-23 signaling (Floss et al. 2016).
R-HSA-8950740 (Reactome) Interleukin-12 subunit alpha (IL12A, IL12p35) binds Interleukin-27 subunit beta (EBI3) forming the Interleukin-35 heterodimeric complex (IL12A:EBI3)(Devergne et al.). When expressed alone, human EBI3 is associated with the endoplasmic reticulum (ER) resident molecular chaperone calnexin (CANX) and is retained in the ER (Devergne et al. 1997). Co-expression of IL27 and EBI3 enables formation of IL27:EBI3, allowing secretion (Pflanz et al. 2002).

This is a Black Box event because there is not reported wich reaction occurs first: the association of IL12A to EBI3:CANX and later the Interleukin-35 heterodimeric protein formation.
R-HSA-8950741 (Reactome) Interleukin-23 is secreted to the extracellular region.

T helper 1 cell (Th1) cytokines such as Interferon-gamma (IFNG) and Interleukin-12 (IL12) are transported through the tubulovesicular system to small secretory vesicles from their sites of storage in crystalloid granules (Spencer et al. 2009, Melo et al. 2005). In neutrophils the precise intracellular location of cytokines and chemokines is unknown, although histological examination of mature peripheral neutrophils suggests that Interleukin-6, IL12 and C-X-C motif chemokine 2 (CXCL2) may be stored within secretory vesicles or tertiary granules (Denkers et al. 2003, Stanley & Lacy 2010).

This reaction is a black box event because we know this Interleukin-23 heterodimeric protein is secreted but do not know the storage compartment and mechanism involved in the traslocation.
R-HSA-8950752 (Reactome) Inferred from mouse:
Interleukin-12 (IL12) translocates from the Golgi to the late endosome.

IL12 has been localized in late endocytic vesicles identified by the marker protein Vesicle-associated membrane protein 7 (VAMP7).
Immunoelectron microscopy on cells expressing p35-SV5 (recombinant murine Il12a with simian virus 5) revealed that the majority of Il12a was associated with Golgi stacks and nearby tubovesicular membranes representing the trans-Golgi Network (Chiaruttini et al. 2016). A fraction of the protein was contained in vesicles and tubules associated with late-endosomes/lysosomes. This indicates that post-golgi trafficking of bioactive IL12 in dendritic cells utilizes late endocytic vesicles.
R-HSA-8950757 (Reactome) Phosphorylated residues in the cytoplasmic region of Interleukin-12 receptor subunit beta 2 (IL12RB2) enable binding and activation of Signal transducer and activator of transcription 4 (STAT4) by means of Tyrosine-protein kinase JAK2 (JAK2).
STAT4 was found to bind only phosphorylated tyrosine-800, and not to phosphorylated tyrosines 678 or 767 when phosphorylated. Although required, phosphorylated tyrosine-800 was not sufficient for binding of STAT4, as other residues in IL12RB2, specifically at -4, -1 and +1 relative to the tyrosine, contribute to the specificity of STAT4 binding (Yao et al. 1999).
As the pattern of phosphorylations required for receptor activation is unknown, this is a black box event.
R-HSA-8950766 (Reactome) Interleukin-27 receptor subunit alpha (IL27RA, WSX1) can interact with itself. Co-expression in HEK- 293 cells followed by immunoprecipitation with epitope tag antibodies revealed that IL27RA forms homodimers. Immunoblotting for JAK proteins and Interleukin-6 receptor beta (IL6ST, gp130) did not detect these as part of the IL27RA-containing complex (Pradhan et al. 2010).

A deletion mutation has been described to enhance homodimeric Interleukin-27 receptor formation (IL27RA/IL27RA) (Lambert et al. 2011).
R-HSA-8950778 (Reactome) Cell stimulation by Interleukin-12 (IL12) leads to formation of Signal transducer and activator of transcription 4 (STAT4) dimers but not heterodimers with STAT1 or STAT3 (Naeger et al. 1999).
STAT4 is required to mediate IL12 effects and is crucial for T cell helper 1 (Th1) development and efficient Interferon gamma (IFNG) production, as shown by STAT4 knock-out studies (Kaplan et al. 1996, Thierfelder et al. 1996). STAT4 is activated by the interaction of IL12 with the interleukin-12 receptor. The interaction of the STAT4 SH2 domain is specific for the peptide sequence pYLPSNID, which contains tyrosine 800 in the Interleukin-12 receptor beta 2 subunit (IL12RB2). This tyrosine is required for STAT4 DNA binding activity and transcriptional activation of the Interferon regulatory factor 1(IRF1) gene.

STAT4 is not capable of binding other peptide sequences at tyrosine residues 678 or 767 of IL12RB2 and these peptides are not required for STAT4 activation.
The Interleukin-12 receptor peptide sequence pYLPSNID appears to be a specific binding site for STAT4, other STATs, including STAT1, which has a closely related SH2 domain, do not recognize pYLPSNID peptides (Naeger et al. 1999).
R-HSA-8950780 (Reactome) Interleukin-23 (IL23) signaling predominantly leads to formation of Signal transducer and activator of transcription 3 (STAT3) homodimers while also heterodimers of STAT3 and STAT4 can also be formed (Parham et al. 2002). The STAT4 phosphorylation induced by IL23 is much weaker than induced in response to Interleukin-12.
R-HSA-8950782 (Reactome) Monocytes express the Interleukin-27 receptor and in response to Interleukin-27 induce Signal transducer and activator of transcription 1-alpha/beta (STAT1) and STAT3 phosphorylation (Pflanz et al. 2004). Interleukin-27 can induce formation of STAT1/STAT3 heterodimers (Guzzo et al. 2010, Hirahara et al. 2015). Nuclear factor NF-kappa-B (NFkB) is activated by Interleukin-27 stimulation in response to STAT1/STAT3 activation and is essential for Interleukin-27 to activate the production of cytokines (Guzzo et al. 2010).
R-HSA-8952749 (Reactome) Signal transducer and activator of transcription 4 (STAT4) is believed to bind Interleukin-23 receptor (IL23R) in response to Interleukin-23 (IL23). The sequence GY484KPQIS in IL23R is thought to be the STAT4 binding site as it resembles the STAT4 binding motif in IL12RB2 (Naeger at al. 1999, Yao et al. 1999). This is a black box event because there is no direct evidence of STAT4 binding in response to IL23. Note that theris no evidence to suggest that STAT3 binding precedes STAT4 association.
R-HSA-8952807 (Reactome) Phosphorylated Signal transducer and activator of transcription 4 (STAT4) dissociates from the receptor, dimerizes, translocates to the nucleus and binds to STAT target sequences in Interleukin-12 responsive genes (Cho et al.1996, Bacon et al. 1995).
This is a Black Box Event since the exact mechanism of association and dissociation of STATs is not described.
R-HSA-8952823 (Reactome) Activated Signal transducer and activator of transcription 4 (STAT4) and STAT3 are released as subunits after Interleukin-23 (IL23) binds the Interleukin-23 heterodimeric receptor (Parham et al. 2002, Silvanesan et al. 2016).
This is a Black box event since the exact mechanisms of STAT3 and STAT4 binding, phosphorylation, dissociation and dimerization are unknown.
R-HSA-8981093 (Reactome) Association kinetics based on competition experiments with Iodine125-labeled Interleukin-12 (IL12) in human PHA-activated lymphoblasts suggested that upon binding of IL12 to the IL-12 receptor the IL12 and probably its receptor are subsequently internalized (Chizzonite et al. 1992). Using confocal laser microscopy in human B cells and primary T cells it was shown that after binding of IL12 to the IL-12 receptor heterodimer IL12:IL12RB1:IL12RB2 is indeed internalised into the cell (Durali et al. 2003). This is a black box event because the mechanism is uncertain.
R-HSA-8983518 (Reactome) 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.
R-HSA-8983519 (Reactome) Interleukin 35 (IL35) is a heteromeric complex conformed by Interleukin 12 subunit alpha (IL12A) and Interleukin 27 subunit alpha (IL27). IL35 may presumably stimulate Janus Kinase (JAK) bound homodimers of Interleukin 12 receptor beta 2 (IL12RB2). JAKs are believed to be associated with the receptor before receptor activation (Behrmann et al., 2004). Subsequently, this triggers the phosphorylation of STAT4 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.
R-HSA-8983834 (Reactome) Interleukin 35 (IL35) may presumably signal via a complex that includes Tyrosine protein kinase JAK1 (JAK1) and JAK2 associated with Interleukin 6 receptor beta subunit (IL6ST) dimers (Collison et al. 2012). These JAKs are believed to phosphorylate Signal transducer and activator of transcription 1 (STAT) (Stark GR and Darnell JE, 2012). As the series of events that induces JAK/STAT phosphorylation events in response to IL35 are not clear, this event is represented as a black box.
R-HSA-8983835 (Reactome) Interleukin-35 (IL35) binding activates the IL35 receptor complex and facilitates Tyrosine-protein kinase JAK (JAK) phosphorylation. Subsequently, Signal transducer and activator of transcription 1-alpha/beta (STAT1) binds to the receptor complex and is activated by tyrosine phosphorylation (Collison et al. 2012). Although it is known that JAKs are involved in STATs phosphorylation (Stark GR and Darnell JE, 2012), it is not clear how other components of the IL35 receptor complex contribute to STAT1 phosphorylation. For this reason, this event is assigned a black box status.
R-HSA-8983841 (Reactome) Interleukin-35 (IL35) binding activates the IL35 receptor complex and facilitates JAKs phosphorylation. Subsequently, Signal transducer and activator of transcription 1-alpha/beta (STAT1) binds to the receptor complex and is activated by tyrosine phosphorylation (Collison et al. 2012). This is a black box event because the receptor subunit responsible for STAT1 binding to the receptor is unclear.
R-HSA-8983845 (Reactome) Interleukin-35 (IL35) can signal via IL35 receptors triggering the JAK/STAT pathway downstream. Signal transducer and activator of transcription 1-alpha/beta (STAT1) binds to the JAK associated-IL35 receptor complex and is activated via phosphorylations. Subsequently, phosphorylated p-STAT1 dissociates from the receptor complex (Collison et al. 2012). This is a black box event because there is no literature evidence about the exact mechanism of the release of STAT1 from the receptor complex.
R-HSA-8983870 (Reactome) Interleukin 35 (IL35) may presumably signal via a complex that includes Tyrosine protein kinase JAK2 (JAK2) associated with Interleukin 12 receptor beta 2 (IL12RB2) dimers (Collison et al. 2012). JAKs are believed to phosphorylate Signal transducers and activator of transcription (STATs) (Stark GR and Darnell JE, 2012). As the series of events that induce JAK/STAT phosphorylation events in response to IL35 are not clear, this event is represented as a black box.
R-HSA-8983872 (Reactome) Interleukin 35 (IL35) binding activates the IL35 receptor complex and may facilitate Tyrosine protein kinase JAK (JAK) phosphorylation. Subsequently, Signal transducer and activator of transcription 4 alpha/beta (STAT4) may bind to the receptor complex and is activated by tyrosine phosphorylation (Collison et al. 2012). JAK2 is known to be involved in the phosphorylation of STAT1 (Higashi T et al., 2005).
R-HSA-8983876 (Reactome) Interleukin-35 (IL35) binding activates the IL35 receptor complex and facilitates JAKs phosphorylation. Subsequently, Signal transducer and activator of transcription 4-alpha/beta (STAT4) binds to the receptor complex and is activated by tyrosine phosphorylation (Collison et al. 2012). This is a black box event because the receptor subunit responsible for STAT4 binding to the receptor is unclear.
R-HSA-8983878 (Reactome) Interleukin-35 (IL35) can signal via IL35 receptors triggering the JAK/STAT pathway downstream. Signal transducer and activator of transcription 4-alpha/beta (STAT4) binds to the JAK associated-IL35 receptor complex and are activated via phosphorylations. Subsequently, phosphorylated p-STAT4 dissociates from the receptor complex (Collison et al. 2012). This is a black box event because there is no literature evidence about the exact mechanism of the release of STAT4 from the receptor complex.
R-HSA-8983983 (Reactome) Signal transducer and activator of transcription 1-alpha/beta(STAT1) and Signal transducer and activator of transcription 4 (STAT4) after phosphorylation dissociates from the complex of ligand receptor and will dimerize (Delgoffe & Vignali 2013). This is a Black Box event because the mechanism of the release of STAT1 and STAT4 from the receptor complex is unclear. However, it is reported that simultaneous activation of IL12RB2 or IL6ST homodimer receptors do not promote the formation of pSTAT1:pSTAT4 and only the activation of the IL12RB2:IL6ST heteromeric receptor favours pSTAT1:pSTAT4 formation. For this reason, STAT1 and STAT4 are simultaneously considered in the binding, activation and release events.
R-HSA-8983996 (Reactome) Interleukin-35 (IL35) binding activates the IL35 receptor complex and facilitates JAKs phosphorylation. Subsequently, Signal transducer and activator of transcription 1-alpha/beta (STAT1) and STAT4 bind to the receptor complex and are activated by tyrosine phosphorylation (Collison et al. 2012). This is a black box event because the receptor subunit responsible for STAT4 binding to the receptor is unclear. However, it is reported that simultaneous activation of IL12RB2 or IL6ST homodimer receptors do not promote the formation of pSTAT1:pSTAT4 and only the activation of the IL12RB2:IL6ST heteromeric receptor favours pSTAT1:pSTAT4 formation. For this reason, STAT1 and STAT4 are simultaneously considered in the binding, activation and release events.
R-HSA-8984001 (Reactome) Interleukin 35 (IL35) is a heteromeric complex of Interleukin 12 subunit alpha (IL12A) and Interleukin 27 subunit alpha (IL27). IL35 can trigger the activation of the Janus Kinase (JAK) bound heterodimeric receptor composed of Interleukin 27 receptor subunit alpha (Il27RA) and Interleukin 12 recetor subunit beta 2 (IL12RB2). JAKs are believed to be associated with the receptor before receptor activation (Behrmann et al., 2004). Consequently, IL12RB2:IL27RA facilitates the phosphorylation of STAT1:STAT3 heteromer downstream. Physiologically, this may result in the expansion of regulatory B cells and suppression of T and B cell proliferation. As it is not clear whether the dimeric receptor can form in the absence of ligand, formation of the receptor dimer is represented here as a black box event.
R-HSA-8984012 (Reactome) Interleukin 35 (IL35) presumably signal via a complex that includes Interleukin 27 receptor subunit alpha (Il27RA), Interleukin 12 receptor subunit beta 2 (IL12RB2) and the associated Tyrosine protein kinase JAK1 (JAK1) and JAK2 (Wang et al. 2014). Downstream, these JAKs are believed to phosphorylate Signal transducer and activator of transcription 1 (STAT1) and STAT3 (Stark GR and Darnell JE, 2012). As the series of events that induces JAK/STAT phosphorylation events in response to IL35 are not clear, this event is represented as a black box.
R-HSA-8984014 (Reactome) Interleukin 35 (IL35) binding activates the IL35 receptor complex and may presumably facilitate Tyrosine protein kinase JAK (JAK) phosphorylation. Subsequently, Signal transducer and activator of transcription 1 alpha/beta (STAT1) and Signal transducer and activator of transcription 3 alpha/beta (STAT3) may bind to the receptor complex and are activated by tyrosine phosphorylation. Although it is known that JAKs are involved in STATs phosphorylation (Stark GR and Darnell JE, 2012), it is not clear how other components of the IL35 receptor complex contribute to STAT1/STAT3 phosphorylation. For this reason, this event is assigned a black box status.
R-HSA-8984021 (Reactome) Interleukin 35 (IL35) binding activates the IL35 receptor complex and facilitates JAKs phosphorylation. Subsequently, Signal transducer and activator of transcription 1 alpha/beta (STAT1) and Signal transducer and activator of transcription 3 alpha/beta (STAT3) bind to the receptor complex and are activated by tyrosine phosphorylation (Wang et al. 2014). This is a black box event because the receptor subunit responsible for STAT1 and STAT3 binding to the receptor is unclear.
R-HSA-8984023 (Reactome) Interleukin 35 (IL35) can signal via IL35 receptors triggering the JAK/STAT pathway downstream. Signal transducer and activator of transcription 1 alpha/beta (STAT1) and Signal transducer and activator of transcription 3 alpha/beta (STAT3) bind to the JAK associated IL35 receptor complex and are activated via phosphorylations. Subsequently, phosphorylated p STAT1:p STAT3 dissociates from the receptor complex (Wang et al. 2014). This is a black box event because there is no literature evidence about the exact mechanism of the release of STAT1 and STAT3 from the receptor complex.
R-HSA-8984963 (Reactome) Interleukin-35 (IL35) is a complex conformed by Interleukin-12 subunit alpha (IL12A) and Interleukin-27 subunit alpha (IL27). IL35 can induce heterodimers of Interleukin-6 receptor beta precursor (IL6ST) and Interleukin-12 receptor beta 2 (IL12RB2). Consequently, heteromeric Signal transducer and activator of transcription 1-alpha/beta (STAT1) and Signal transducer and activator of transcription 4 (STAT4) are phosphorylated. Subsequently, this STAT1:STAT4 complex can translocate into the nucleus and bind to promoter regions of IL27 thereby facilitating the protein expression. Thus, by inducing the expression of itself, a positive feedback regulation is achieved in the IL35 signalling pathway. This is a black box event because the intermediate steps of IL27 transcription/translation are omitted.
R-HSA-8984964 (Reactome) Interleukin-35 (IL35) is a complex conformed by Interleukin-12 subunit alpha (IL12A) and Interleukin-27 subunit alpha (IL27). IL35 can induce heterodimers of Interleukin-6 receptor beta precursor (IL6ST) and Interleukin-12 receptor beta 2 (IL12RB2). Consequently, heteromeric Signal transducer and activator of transcription 1-alpha/beta (STAT1) and Signal transducer and activator of transcription 4 (STAT4) are phosphorylated. Subsequently, this STAT1:STAT4 complex can translocate into the nucleus and bind to promoter regions of IL12A thereby facilitating the protein expression. Thus, by inducing the expression of itself, a positive feedback regulation is achieved in the IL35 signalling pathway. This is a black box event because the intermediate steps of IL12A transcription/translation are omitted.
STAT1R-HSA-8950518 (Reactome)
STAT1R-HSA-8983841 (Reactome)
STAT1R-HSA-8983996 (Reactome)
STAT1R-HSA-8984021 (Reactome)
STAT3R-HSA-8950518 (Reactome)
STAT3R-HSA-8950583 (Reactome)
STAT3R-HSA-8984021 (Reactome)
STAT4R-HSA-8950448 (Reactome)
STAT4R-HSA-8952749 (Reactome)
STAT4R-HSA-8983876 (Reactome)
STAT4R-HSA-8983996 (Reactome)
TYK2R-HSA-8950057 (Reactome)
VAMP7ArrowR-HSA-8950347 (Reactome)
VAMP7TBarR-HSA-8950347 (Reactome)
Y963-STAT4 dimerArrowR-HSA-8950181 (Reactome)
p-STAT1:p-STAT4ArrowR-HSA-8983983 (Reactome)
p-STAT1:p-STAT4R-HSA-8950522 (Reactome)
p-STAT1ArrowR-HSA-8983845 (Reactome)
p-STAT1ArrowR-HSA-8984023 (Reactome)
p-STAT3ArrowR-HSA-8984023 (Reactome)
p-STAT4ArrowR-HSA-8983878 (Reactome)
p-Y693-STAT4 dimerArrowR-HSA-8950778 (Reactome)
p-Y693-STAT4 dimerR-HSA-8950181 (Reactome)
p-Y693-STAT4:p-Y701-STAT1:EBI3 geneArrowR-HSA-8984963 (Reactome)
p-Y693-STAT4:p-Y701-STAT1:IL12A geneArrowR-HSA-8984964 (Reactome)
p-Y693-STAT4:p-Y701-STAT1ArrowR-HSA-8950522 (Reactome)
p-Y693-STAT4ArrowR-HSA-8952807 (Reactome)
p-Y693-STAT4ArrowR-HSA-8952823 (Reactome)
p-Y693-STAT4R-HSA-8950778 (Reactome)
p-Y693-STAT4R-HSA-8950780 (Reactome)
p-Y701-STAT1:p-Y705-STAT3:IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2ArrowR-HSA-8950485 (Reactome)
p-Y701-STAT1:p-Y705-STAT3:IL27:EBI3:p-Y611-IL27RA:p-JAK1:p-Y-IL6ST:p-JAK1,p-JAK2,p-TYK2R-HSA-8950441 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ArrowR-HSA-8950733 (Reactome)
p-Y701-STAT1:p-Y705-STAT3ArrowR-HSA-8950782 (Reactome)
p-Y701-STAT1:p-Y705-STAT3R-HSA-8950733 (Reactome)
p-Y701-STAT1ArrowR-HSA-8950441 (Reactome)
p-Y701-STAT1R-HSA-8950782 (Reactome)
p-Y705-STAT3:p-Y693-STAT4ArrowR-HSA-8950724 (Reactome)
p-Y705-STAT3:p-Y693-STAT4ArrowR-HSA-8950780 (Reactome)
p-Y705-STAT3:p-Y693-STAT4R-HSA-8950724 (Reactome)
p-Y705-STAT3ArrowR-HSA-8950441 (Reactome)
p-Y705-STAT3ArrowR-HSA-8952823 (Reactome)
p-Y705-STAT3R-HSA-8950780 (Reactome)
p-Y705-STAT3R-HSA-8950782 (Reactome)
sIL27RAArrowR-HSA-8950271 (Reactome)
sIL27RAR-HSA-8950271 (Reactome)
sIL27RATBarR-HSA-448427 (Reactome)
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