Interferon gamma signaling (Homo sapiens)

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Interferon-gamma (IFN-gamma) belongs to the type II interferon family and is secreted by activated immune cells-primarily T and NK cells, but also B-cells and APC. INFG exerts its effect on cells by interacting with the specific IFN-gamma receptor (IFNGR). IFNGR consists of two chains, namely IFNGR1 (also known as the IFNGR alpha chain) and IFNGR2 (also known as the IFNGR beta chain). IFNGR1 is the ligand binding receptor and is required but not sufficient for signal transduction, whereas IFNGR2 do not bind IFNG independently but mainly plays a role in IFNG signaling and is generally the limiting factor in IFNG responsiveness. Both IFNGR chains lack intrinsic kinase/phosphatase activity and thus rely on other signaling proteins like Janus-activated kinase 1 (JAK1), JAK2 and Signal transducer and activator of transcription 1 (STAT-1) for signal transduction. IFNGR complex in its resting state is a preformed tetramer and upon IFNG association undergoes a conformational change. This conformational change induces the phosphorylation and activation of JAK1, JAK2, and STAT1 which in turn induces genes containing the gamma-interferon activation sequence (GAS) in the promoter. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 877300
Reactome version: 61
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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  1. Liao J, Fu Y, Shuai K.; ''Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction.''; PubMed
  2. Walter MR, Windsor WT, Nagabhushan TL, Lundell DJ, Lunn CA, Zauodny PJ, Narula SK.; ''Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor.''; PubMed
  3. Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, Cook JR, Garotta G, Silvennoinen O, Ihle JN.; ''Interaction between the components of the interferon gamma receptor complex.''; PubMed
  4. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A.; ''The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop.''; PubMed
  5. Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A.; ''Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain.''; PubMed
  6. Fountoulakis M, Zulauf M, Lustig A, Garotta G.; ''Stoichiometry of interaction between interferon gamma and its receptor.''; PubMed
  7. Martinez FO, Gordon S, Locati M, Mantovani A.; ''Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression.''; PubMed
  8. Krause CD, Lavnikova N, Xie J, Mei E, Mirochnitchenko OV, Jia Y, Hochstrasser RM, Pestka S.; ''Preassembly and ligand-induced restructuring of the chains of the IFN-gamma receptor complex: the roles of Jak kinases, Stat1 and the receptor chains.''; PubMed
  9. Stratowa C, Audette M.; ''Transcriptional regulation of the human intercellular adhesion molecule-1 gene: a short overview.''; PubMed
  10. Briscoe J, Rogers NC, Witthuhn BA, Watling D, Harpur AG, Wilks AF, Stark GR, Ihle JN, Kerr IM.; ''Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state.''; PubMed
  11. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE.; ''Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions.''; PubMed
  12. Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C.; ''Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity.''; PubMed
  13. Krause CD, Mei E, Xie J, Jia Y, Bopp MA, Hochstrasser RM, Pestka S.; ''Seeing the light: preassembly and ligand-induced changes of the interferon gamma receptor complex in cells.''; PubMed
  14. Rajsbaum R, Stoye JP, O'Garra A.; ''Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells.''; PubMed
  15. Igarashi K, Garotta G, Ozmen L, Ziemiecki A, Wilks AF, Harpur AG, Larner AC, Finbloom DS.; ''Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor.''; PubMed
  16. Wenta N, Strauss H, Meyer S, Vinkemeier U.; ''Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations.''; PubMed
  17. Pearse RN, Feinman R, Shuai K, Darnell JE, Ravetch JV.; ''Interferon gamma-induced transcription of the high-affinity Fc receptor for IgG requires assembly of a complex that includes the 91-kDa subunit of transcription factor ISGF3.''; PubMed
  18. Schroder K, Hertzog PJ, Ravasi T, Hume DA.; ''Interferon-gamma: an overview of signals, mechanisms and functions.''; PubMed
  19. Rosenman SJ, Shrikant P, Dubb L, Benveniste EN, Ransohoff RM.; ''Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines.''; PubMed
  20. Lew DJ, Decker T, Strehlow I, Darnell JE.; ''Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons.''; PubMed
  21. Greenlund AC, Morales MO, Viviano BL, Yan H, Krolewski J, Schreiber RD.; ''Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process.''; PubMed
  22. Ouellet S, Müller E, Rola-Pleszczynski M.; ''IFN-gamma up-regulates platelet-activating factor receptor gene expression in human monocytes.''; PubMed
  23. Huang F, Xiao H, Sun BL, Yang RG.; ''Characterization of TRIM62 as a RING finger E3 ubiquitin ligase and its subcellular localization.''; PubMed
  24. Mowen K, David M.; ''Regulation of STAT1 nuclear export by Jak1.''; PubMed
  25. Palvimo JJ.; ''PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription.''; PubMed
  26. Argetsinger LS, Stuckey JA, Robertson SA, Koleva RI, Cline JM, Marto JA, Myers MG, Carter-Su C.; ''Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity.''; PubMed
  27. Shuai K, Stark GR, Kerr IM, Darnell JE.; ''A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma.''; PubMed
  28. Quelle FW, Thierfelder W, Witthuhn BA, Tang B, Cohen S, Ihle JN.; ''Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor.''; PubMed
  29. Decker T, Lew DJ, Mirkovitch J, Darnell JE.; ''Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor.''; PubMed
  30. Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler FK, Ealick SE.; ''Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex.''; PubMed
  31. Gough DJ, Levy DE, Johnstone RW, Clarke CJ.; ''IFNgamma signaling-does it mean JAK-STAT?''; PubMed
  32. Aaronson DS, Horvath CM.; ''A road map for those who don't know JAK-STAT.''; PubMed
  33. Bach EA, Aguet M, Schreiber RD.; ''The IFN gamma receptor: a paradigm for cytokine receptor signaling.''; PubMed
  34. Nair JS, DaFonseca CJ, Tjernberg A, Sun W, Darnell JE, Chait BT, Zhang JJ.; ''Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma.''; PubMed
  35. Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE.; ''Three-dimensional structure of recombinant human interferon-gamma.''; PubMed
  36. Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Jänne OA, Palvimo JJ, Silvennoinen O.; ''PIAS proteins promote SUMO-1 conjugation to STAT1.''; PubMed
  37. Costa-Pereira AP, Hermanns HM, Is'harc H, Williams TM, Watling D, Arulampalam V, Newman SJ, Heinrich PC, Kerr IM.; ''Signaling through a mutant IFN-gamma receptor.''; PubMed
  38. Feng J, Witthuhn BA, Matsuda T, Kohlhuber F, Kerr IM, Ihle JN.; ''Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.''; PubMed
  39. Greenlund AC, Farrar MA, Viviano BL, Schreiber RD.; ''Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91).''; PubMed
  40. Shuai K, Schindler C, Prezioso VR, Darnell JE.; ''Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.''; PubMed
  41. Rupper AC, Cardelli JA.; ''Induction of guanylate binding protein 5 by gamma interferon increases susceptibility to Salmonella enterica serovar Typhimurium-induced pyroptosis in RAW 264.7 cells.''; PubMed
  42. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, Shuai K.; ''Identification of a nuclear Stat1 protein tyrosine phosphatase.''; PubMed
  43. Matsuda T, Feng J, Witthuhn BA, Sekine Y, Ihle JN.; ''Determination of the transphosphorylation sites of Jak2 kinase.''; PubMed
  44. Sakatsume M, Igarashi K, Winestock KD, Garotta G, Larner AC, Finbloom DS.; ''The Jak kinases differentially associate with the alpha and beta (accessory factor) chains of the interferon gamma receptor to form a functional receptor unit capable of activating STAT transcription factors.''; PubMed
  45. Strehlow I, Decker T.; ''Transcriptional induction of IFN-gamma-responsive genes is modulated by DNA surrounding the interferon stimulation response element.''; PubMed
  46. DeVries TA, Kalkofen RL, Matassa AA, Reyland ME.; ''Protein kinase Cdelta regulates apoptosis via activation of STAT1.''; PubMed
  47. Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ.; ''The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3.''; PubMed
  48. Kaplan DH, Greenlund AC, Tanner JW, Shaw AS, Schreiber RD.; ''Identification of an interferon-gamma receptor alpha chain sequence required for JAK-1 binding.''; PubMed
  49. McBride KM, Reich NC.; ''The ins and outs of STAT1 nuclear transport.''; PubMed
  50. Pestka S, Kotenko SV, Muthukumaran G, Izotova LS, Cook JR, Garotta G.; ''The interferon gamma (IFN-gamma) receptor: a paradigm for the multichain cytokine receptor.''; PubMed
  51. Ozato K, Shin DM, Chang TH, Morse HC.; ''TRIM family proteins and their emerging roles in innate immunity.''; PubMed
  52. Boehm U, Klamp T, Groot M, Howard JC.; ''Cellular responses to interferon-gamma.''; PubMed


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93905view13:44, 16 August 2017ReactomeTeamreactome version 61
93478view11:24, 9 August 2017ReactomeTeamreactome version 61
86576view09:21, 11 July 2016ReactomeTeamreactome version 56
83234view10:27, 18 November 2015ReactomeTeamVersion54
81633view13:10, 21 August 2015ReactomeTeamVersion53
77096view08:39, 17 July 2014ReactomeTeamFixed remaining interactions
76802view12:18, 16 July 2014ReactomeTeamFixed remaining interactions
76125view10:19, 11 June 2014ReactomeTeamRe-fixing comment source
75837view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75198view09:43, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74845view10:07, 30 April 2014ReactomeTeamReactome46
44865view09:58, 6 October 2011MartijnVanIerselOntology Term : 'immune response pathway' added !
42056view21:53, 4 March 2011MaintBotAutomatic update
39862view05:53, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
B2M(21-119)ProteinP61769 (Uniprot-TrEMBL)
CD44 ProteinP16070 (Uniprot-TrEMBL)
CIITAProteinP33076 (Uniprot-TrEMBL)
CaMKII and PKC-deltaComplexR-HSA-909568 (Reactome)
Class I MHC heavy chain (MHC HC)ComplexR-HSA-983117 (Reactome)
FCGR1A ProteinP12314 (Uniprot-TrEMBL)
FCGR1B ProteinQ92637 (Uniprot-TrEMBL)
FCGRAComplexR-HSA-1031694 (Reactome)
GAF bound to GAS promoter elementComplexR-HSA-1031710 (Reactome)
GAS promoter region

in IFNG-regulated

R-NUL-1031708 (Reactome)
GAS promoter region in IFNG-regulated genes R-NUL-1031708 (Reactome)
GBP1 ProteinP32455 (Uniprot-TrEMBL)
GBP2 ProteinP32456 (Uniprot-TrEMBL)
GBP3 ProteinQ9H0R5 (Uniprot-TrEMBL)
GBP4 ProteinQ96PP9 (Uniprot-TrEMBL)
GBP5 ProteinQ96PP8 (Uniprot-TrEMBL)
GBP6 ProteinQ6ZN66 (Uniprot-TrEMBL)
GBP7 ProteinQ8N8V2 (Uniprot-TrEMBL)
GBPComplexR-HSA-1031695 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
HLA class I histocompatibility antigen, A-1 alpha chain precursor ProteinP30443 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-11 alpha chain ProteinP13746 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-2 alpha chain ProteinP01892 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-23 alpha chain ProteinP30447 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-24 alpha chain ProteinP05534 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-25 alpha chain ProteinP18462 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-26 alpha chain ProteinP30450 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-29 alpha chain ProteinP30512 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-3 alpha chain precursor ProteinP04439 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-30 alpha chain ProteinP16188 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-31 alpha chain ProteinP16189 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-32 alpha chain ProteinP10314 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-33 alpha chain ProteinP16190 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-34 alpha chain ProteinP30453 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-36 alpha chain ProteinP30455 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-43 alpha chain ProteinP30456 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-66 alpha chain ProteinP30457 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-68 alpha chain ProteinP01891 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-69 alpha chain ProteinP10316 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-74 alpha chain ProteinP30459 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, A-80 alpha chain ProteinQ09160 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-1 alpha chain ProteinP30499 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-12 alpha chain ProteinP30508 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-14 alpha chain ProteinP30510 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-15 alpha chain ProteinQ07000 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-16 alpha chain ProteinQ29960 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-17 alpha chain ProteinQ95604 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-18 alpha chain ProteinQ29865 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-2 alpha chain ProteinP30501 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-3 alpha chain precursor ProteinP04222 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-4 alpha chain precursor ProteinP30504 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-5 alpha chain precursor ProteinQ9TNN7 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-6 alpha chain precursor ProteinQ29963 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-7 alpha chain precursor ProteinP10321 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, Cw-8 alpha chain ProteinP30505 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, E alpha chain precursor ProteinP13747 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, alpha chain F precursor ProteinP30511 (Uniprot-TrEMBL)
HLA class I histocompatibility antigen, alpha chain G precursor ProteinP17693 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DP ProteinP04440 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DP alpha chain precursor ProteinP20036 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01906 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01909 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQ beta 2 chain ProteinP05538 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DQB1*0602 beta chain precursor ProteinP01920 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR alpha chain precursor ProteinP01903 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 4 chain ProteinP13762 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR beta 5 chain ProteinQ30154 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DR-1 beta chain precursor ProteinP01912 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-1 beta chain ProteinP04229 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-10 beta chain ProteinQ30167 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-11 beta chain ProteinP20039 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-12 beta chain ProteinQ95IE3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-13 beta chain ProteinQ5Y7A7 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-14 beta chain ProteinQ9GIY3 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-15 beta chain ProteinP01911 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-16 beta chain ProteinQ29974 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-4 beta chain ProteinP13760 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-7 beta chain ProteinP13761 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-8 beta chain ProteinQ30134 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB1-9 beta chain precursor ProteinQ9TQE0 (Uniprot-TrEMBL)
HLA class II histocompatibility antigen, DRB3-1 beta chain precursor ProteinP79483 (Uniprot-TrEMBL)
HLA-B ProteinP30486 (Uniprot-TrEMBL)
HLA-H ProteinP01893 (Uniprot-TrEMBL)
ICAM1 ProteinP05362 (Uniprot-TrEMBL)
IFI30ProteinP13284 (Uniprot-TrEMBL)
IFN-gamma upregulated CAMsComplexR-HSA-1031690 (Reactome)
IFNG ProteinP01579 (Uniprot-TrEMBL)
IFNG homodimerComplexR-HSA-873823 (Reactome)
IFNG-activated factor (GAF)ComplexR-HSA-873824 (Reactome)
IFNG-activated factor (GAF)ComplexR-HSA-873827 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2ComplexR-HSA-873829 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3ComplexR-HSA-873821 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2ComplexR-HSA-873811 (Reactome)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2ComplexR-HSA-873820 (Reactome)
IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2ComplexR-HSA-873814 (Reactome)
IFNGR1 ProteinP15260 (Uniprot-TrEMBL)
IFNGR1:JAK1:INFG2:JAK2ComplexR-HSA-873810 (Reactome)
IFNGR2 ProteinP38484 (Uniprot-TrEMBL)
INFG induced TRIMsComplexR-HSA-5624346 (Reactome)
IRF 1-9ComplexR-HSA-1015695 (Reactome)
IRF1 ProteinP10914 (Uniprot-TrEMBL)
IRF2 ProteinP14316 (Uniprot-TrEMBL)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF4 ProteinQ15306 (Uniprot-TrEMBL)
IRF5 ProteinQ13568 (Uniprot-TrEMBL)
IRF6 ProteinO14896 (Uniprot-TrEMBL)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
IRF8 ProteinQ02556 (Uniprot-TrEMBL)
IRF9 ProteinQ00978 (Uniprot-TrEMBL)
JAK1 ProteinP23458 (Uniprot-TrEMBL)
JAK2 ProteinO60674 (Uniprot-TrEMBL)
MHC class II alpha/beta dimerComplexR-HSA-2213189 (Reactome)
MID1 ProteinO15344 (Uniprot-TrEMBL)
MT2AProteinP02795 (Uniprot-TrEMBL)
NCAM1 ProteinP13591 (Uniprot-TrEMBL)
OAS proteinsComplexR-HSA-1015696 (Reactome)
OAS1 ProteinP00973 (Uniprot-TrEMBL)
OAS2 ProteinP29728 (Uniprot-TrEMBL)
OAS3 ProteinQ9Y6K5 (Uniprot-TrEMBL)
OASL ProteinQ15646 (Uniprot-TrEMBL)
PIAS1 ProteinO75925 (Uniprot-TrEMBL)
PIAS1ProteinO75925 (Uniprot-TrEMBL)
PML ProteinP29590 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
PRKCD ProteinQ05655 (Uniprot-TrEMBL)
PTAFRProteinP25105 (Uniprot-TrEMBL)
PTPN1 ProteinP18031 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PTPN2-1ProteinP17706-2 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
PTPs-SHP1/2/PTP1BComplexR-HSA-997298 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
SOCS-1 and SOCS-3ComplexR-HSA-877267 (Reactome)
SOCS1 ProteinO15524 (Uniprot-TrEMBL)
SOCS3 ProteinO14543 (Uniprot-TrEMBL)
SP100ProteinP23497 (Uniprot-TrEMBL)
STAT1 bound to p-IFNGR1ComplexR-HSA-873828 (Reactome)
STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
STAT1-1ProteinP42224-1 (Uniprot-TrEMBL)
SUMO1 ProteinP63165 (Uniprot-TrEMBL)
SUMO1ProteinP63165 (Uniprot-TrEMBL)
TRIM10 ProteinQ9UDY6 (Uniprot-TrEMBL)
TRIM14 ProteinQ14142 (Uniprot-TrEMBL)
TRIM17 ProteinQ9Y577 (Uniprot-TrEMBL)
TRIM2 ProteinQ9C040 (Uniprot-TrEMBL)
TRIM21 ProteinP19474 (Uniprot-TrEMBL)
TRIM22 ProteinQ8IYM9 (Uniprot-TrEMBL)
TRIM25 ProteinQ14258 (Uniprot-TrEMBL)
TRIM26 ProteinQ12899 (Uniprot-TrEMBL)
TRIM29 ProteinQ14134 (Uniprot-TrEMBL)
TRIM3 ProteinO75382 (Uniprot-TrEMBL)
TRIM31 ProteinQ9BZY9 (Uniprot-TrEMBL)
TRIM34 ProteinQ9BYJ4 (Uniprot-TrEMBL)
TRIM35 ProteinQ9UPQ4 (Uniprot-TrEMBL)
TRIM38 ProteinO00635 (Uniprot-TrEMBL)
TRIM45 ProteinQ9H8W5 (Uniprot-TrEMBL)
TRIM46 ProteinQ7Z4K8 (Uniprot-TrEMBL)
TRIM48 ProteinQ8IWZ4 (Uniprot-TrEMBL)
TRIM5 ProteinQ9C035 (Uniprot-TrEMBL)
TRIM6 ProteinQ9C030 (Uniprot-TrEMBL)
TRIM62 ProteinQ9BVG3 (Uniprot-TrEMBL)
TRIM68 ProteinQ6AZZ1 (Uniprot-TrEMBL)
TRIM8 ProteinQ9BZR9 (Uniprot-TrEMBL)
VCAM1 ProteinP19320 (Uniprot-TrEMBL)
class I MHC B13 ProteinP30461 (Uniprot-TrEMBL)
class I MHC B14 ProteinP30462 (Uniprot-TrEMBL)
class I MHC B15 ProteinP30464 (Uniprot-TrEMBL)
class I MHC B18 ProteinP30466 (Uniprot-TrEMBL)
class I MHC B27 ProteinP03989 (Uniprot-TrEMBL)
class I MHC B35 ProteinP30685 (Uniprot-TrEMBL)
class I MHC B37 ProteinP18463 (Uniprot-TrEMBL)
class I MHC B38 ProteinQ95365 (Uniprot-TrEMBL)
class I MHC B39 ProteinP30475 (Uniprot-TrEMBL)
class I MHC B40 ProteinQ04826 (Uniprot-TrEMBL)
class I MHC B41 ProteinP30479 (Uniprot-TrEMBL)
class I MHC B42 ProteinP30480 (Uniprot-TrEMBL)
class I MHC B44 ProteinP30481 (Uniprot-TrEMBL)
class I MHC B45 ProteinP30483 (Uniprot-TrEMBL)
class I MHC B46 ProteinP30484 (Uniprot-TrEMBL)
class I MHC B47 ProteinP30485 (Uniprot-TrEMBL)
class I MHC B49 ProteinP30487 (Uniprot-TrEMBL)
class I MHC B50 ProteinP30488 (Uniprot-TrEMBL)
class I MHC B51 ProteinP18464 (Uniprot-TrEMBL)
class I MHC B52 ProteinP30490 (Uniprot-TrEMBL)
class I MHC B53 ProteinP30491 (Uniprot-TrEMBL)
class I MHC B54 ProteinP30492 (Uniprot-TrEMBL)
class I MHC B55 ProteinP30493 (Uniprot-TrEMBL)
class I MHC B56 ProteinP30495 (Uniprot-TrEMBL)
class I MHC B57 ProteinP18465 (Uniprot-TrEMBL)
class I MHC B58 ProteinP10319 (Uniprot-TrEMBL)
class I MHC B59 ProteinQ29940 (Uniprot-TrEMBL)
class I MHC B67 ProteinQ29836 (Uniprot-TrEMBL)
class I MHC B7 ProteinP01889 (Uniprot-TrEMBL)
class I MHC B73 ProteinQ31612 (Uniprot-TrEMBL)
class I MHC B78 ProteinP30498 (Uniprot-TrEMBL)
class I MHC B8 ProteinP30460 (Uniprot-TrEMBL)
class I MHC B81 ProteinQ31610 (Uniprot-TrEMBL)
class I MHC B82 ProteinQ29718 (Uniprot-TrEMBL)
p-S727,Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)
p-STAT1 dimer:PIAS:SUMO1ComplexR-HSA-877297 (Reactome)
p-STAT1 dimer bound to p-IFNGR1ComplexR-HSA-909556 (Reactome)
p-STAT1(Y701) bound to p-IFNGR1ComplexR-HSA-873817 (Reactome)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T287-CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
p-T287-CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
p-T287-CAMK2G ProteinQ13555 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y1007-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y440-IFNGR1 ProteinP15260 (Uniprot-TrEMBL)
p-Y701-STAT1-1 ProteinP42224-1 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-873918 (Reactome)
ADPArrowR-HSA-873919 (Reactome)
ADPArrowR-HSA-873922 (Reactome)
ADPArrowR-HSA-873924 (Reactome)
ADPArrowR-HSA-909552 (Reactome)
ATPR-HSA-873918 (Reactome)
ATPR-HSA-873919 (Reactome)
ATPR-HSA-873922 (Reactome)
ATPR-HSA-873924 (Reactome)
ATPR-HSA-909552 (Reactome)
B2M(21-119)ArrowR-HSA-1031716 (Reactome)
CIITAArrowR-HSA-1031716 (Reactome)
CaMKII and PKC-deltamim-catalysisR-HSA-909552 (Reactome)
Class I MHC heavy chain (MHC HC)ArrowR-HSA-1031716 (Reactome)
FCGRAArrowR-HSA-1031716 (Reactome)
GAF bound to GAS promoter elementArrowR-HSA-1031713 (Reactome)
GAF bound to GAS promoter elementArrowR-HSA-1031716 (Reactome)
GAS promoter region

in IFNG-regulated

R-HSA-1031713 (Reactome)
GBPArrowR-HSA-1031716 (Reactome)
H2OR-HSA-877308 (Reactome)
H2OR-HSA-997326 (Reactome)
IFI30ArrowR-HSA-1031716 (Reactome)
IFN-gamma upregulated CAMsArrowR-HSA-1031716 (Reactome)
IFNG homodimerR-HSA-873926 (Reactome)
IFNG-activated factor (GAF)ArrowR-HSA-873917 (Reactome)
IFNG-activated factor (GAF)ArrowR-HSA-873927 (Reactome)
IFNG-activated factor (GAF)R-HSA-1031713 (Reactome)
IFNG-activated factor (GAF)R-HSA-873917 (Reactome)
IFNG-activated factor (GAF)R-HSA-877281 (Reactome)
IFNG-activated factor (GAF)R-HSA-997326 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2ArrowR-HSA-873926 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2ArrowR-HSA-877308 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2R-HSA-873919 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2mim-catalysisR-HSA-873919 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3ArrowR-HSA-877269 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3TBarR-HSA-873918 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2ArrowR-HSA-873919 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2R-HSA-873918 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2R-HSA-877269 (Reactome)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2mim-catalysisR-HSA-873918 (Reactome)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2ArrowR-HSA-873918 (Reactome)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2R-HSA-873924 (Reactome)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2R-HSA-877308 (Reactome)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2mim-catalysisR-HSA-873924 (Reactome)
IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2ArrowR-HSA-873924 (Reactome)
IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2ArrowR-HSA-873927 (Reactome)
IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2R-HSA-873921 (Reactome)
IFNGR1:JAK1:INFG2:JAK2R-HSA-873926 (Reactome)
INFG induced TRIMsArrowR-HSA-1031716 (Reactome)
IRF 1-9ArrowR-HSA-1031716 (Reactome)
MHC class II alpha/beta dimerArrowR-HSA-1031716 (Reactome)
MT2AArrowR-HSA-1031716 (Reactome)
OAS proteinsArrowR-HSA-1031716 (Reactome)
PIAS1R-HSA-877281 (Reactome)
PMLArrowR-HSA-1031716 (Reactome)
PTAFRArrowR-HSA-1031716 (Reactome)
PTPN2-1mim-catalysisR-HSA-997326 (Reactome)
PTPs-SHP1/2/PTP1Bmim-catalysisR-HSA-877308 (Reactome)
PiArrowR-HSA-877308 (Reactome)
PiArrowR-HSA-997326 (Reactome)
R-HSA-1031713 (Reactome) GAF transcription factor translocated into nucleus binds to defined DNA sequence called GAS (gamma activated sequence) elements in the promoters of IFN-gamma responsive elements and initiate transcription.
R-HSA-1031716 (Reactome) IFN-gamma stimulates gene expression of about 200 genes which include the primary response genes like IRFs, Fc-gamma receptor (FCGR), GBPs (guanylate-binding proteins) and also major histocompatibility complex (MHC) class I and class II molecules, proteins involved in antigen presentation, antiviral proteins like PKR, OAS proteins etc. A wonderful list of most of the IFN-gamma inducible proteins with corresponding literature are mentioned in the review article and the supplementary document by Boehm et al 1997.
R-HSA-873917 (Reactome) Released GAF complex translocates to the nucleus and binds to the gamma-activated sequence (GAS) element present in the promoters of IFNG-regulated genes and induces the transcription of IFNG-responsive genes.
R-HSA-873918 (Reactome) The initial phosphorylation of JAK1 and JAK2 is mediated by JAK2. Autophosphorylated JAK2 may transphopshorylate JAK1 bound to IFNGR1 chain. Tyrosine 1033 in the activation loop of the JAK1 kinase domain may be the target for transphosphorylation (phosphorylation site mentioned here is based on sequence similarity with all the other JAK kinases).
R-HSA-873919 (Reactome) IFN-gamma binding to the receptor complex, induces JAK2 autophosphorylation and activation. Like all protein tyrosine kinases (PTKs) JAK2 activity also depends on the phosphorylation of tandem tyrosine residues within the activation loop that results in the removal of the activation loop from the active site. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity. Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only tyrosine 1007 is represented in the reaction.
R-HSA-873921 (Reactome) The phosphorylated tyrosine residue 440 in the 440YDKPH444 motif on IFNGR1 chain serves as a docking site and recruits STAT1, an SH2 domain-containing transcription factor to the functional receptor unit.
R-HSA-873922 (Reactome) STAT1 pair recruited to the receptor complex is phosphorylated near the C-terminus at residue Y701, probably by JAK2. This phosphorylation enables the STAT1 homodimer formation which is further phosphorylated on residue S727.
R-HSA-873924 (Reactome) The phosphorylated active JAK1 kinase inturn phosphorylates tyrosine residue 440 on each of the IFNGR1 chains to form two adjacent docking sites for the latent STAT1 SH2 domains.
R-HSA-873926 (Reactome) The IFNG receptor complex is a pre-assembled entity, as constitutive interactions are seen between IFNGR1 and IFNGR2, and between two IFNGR2 chains in the absence of ligand IFNG. JAK1 and JAK2 constitutively associate with the intracellular domains of the subunits of the IFNG receptor complex, providing it with tyrosine kinase activity. In unstimulated cells JAK1 preferentially associates with IFNGR1 and while JAK2 associates with IFNGR2 chains. JAK1 enhances the interaction between IFNGR1 and IFNGR2 chains, and thus has a major role in the pre-assembly of the IFNGR complex, in contrast the kinase activity of JAK2 is required to observe any signaling by IFNG.
IFNG binds directly to both the receptor chains IFNGR1 and IFNGR2. IFNGR1 is a high affinity receptor and binds directly to IFNG whereas IFNGR2 binds to IFNG in presence of IFNGR1. According to Krause et al. model IFNG binds to IFNGR1 chains first and then IFNGR2 chains interact with the IFNGR1:IFNG:IFNGR1 complex.
R-HSA-873927 (Reactome) The phosphorylated STAT1 on IFNGR1 chains homodimerize through reciprocal SH2-phosphotyrosine interactions to form p-STAT1 homodimer called gamma-activated-factor (GAF). This phosphorylated STAT1 homodimer disassociates from the receptor complex and translocates to the nucleus.
R-HSA-877269 (Reactome) SOCS-1 and SOCS-3 coprecipitates with JAK kinases upon IFNG stimulation and are able to inhibit the JAK-STAT pathway, although with different affinity and kinetics. SOCS1 and SOCS3 binds to phosphorylated JAK1/2 and prevent the tyrosine kinase activity of JAKs through their kinase inhibitory region (KIR), thereby inhibiting downstream IFNG signaling. SOCS1 may also prevent IFNG signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.
R-HSA-877281 (Reactome) PIAS1 protein interacts directly with phoshorylated STAT1 dimers and inhibit the transcriptional activity of STAT1 by blocking the DNA-binding domain of STAT1. It has also been suggested that PIAS proteins might regulate transcription by promoting small ubiquitin-related modifier (SUMO1) conjugation of STAT1. The significance of STAT1 sumoylation in regulating STAT1 activity is controversial and needs to be clarified.
R-HSA-877308 (Reactome) Protein tyrosine phosphatases (PTPs) SHP1 and SHP2 down regulate the IFNG signaling by dephosphorylating the tyrosine residues critical to the activation of JAK kinases. PTP1B interacts directly with JAK2 but not JAK1 and dephosphorylate the tyrosine Y1007 on JAK2.
R-HSA-909552 (Reactome) Kinases like Protein kinase C delta (PKC-delta) and Calcium/calmodulin-dependent protein kinase II (CaMK II ) can phosphorylate STAT1 at serine 727 (S727). This phosphorylation is not required for STAT1 homodimer formation, nuclear translocation and DNA binding. However, it is essential for the full transcriptional activation of STAT1.
R-HSA-997326 (Reactome) The nuclear isoform of T cell protein tyrosine phosphatase (TC-PTP) referred as TC45 (or TC-PTPa) dephosphorylates p-STAT1 dimer in the nucleus. It can also dephosphorylate p-JAK1/3 in IFNG stimulated cells.
SOCS-1 and SOCS-3R-HSA-877269 (Reactome)
SP100ArrowR-HSA-1031716 (Reactome)
STAT1 bound to p-IFNGR1ArrowR-HSA-873921 (Reactome)
STAT1 bound to p-IFNGR1R-HSA-873922 (Reactome)
STAT1 bound to p-IFNGR1mim-catalysisR-HSA-873922 (Reactome)
STAT1-1ArrowR-HSA-997326 (Reactome)
STAT1-1R-HSA-873921 (Reactome)
SUMO1R-HSA-877281 (Reactome)
TBarR-HSA-873918 (Reactome)
p-STAT1 dimer:PIAS:SUMO1ArrowR-HSA-877281 (Reactome)
p-STAT1 dimer bound to p-IFNGR1ArrowR-HSA-909552 (Reactome)
p-STAT1 dimer bound to p-IFNGR1R-HSA-873927 (Reactome)
p-STAT1(Y701) bound to p-IFNGR1ArrowR-HSA-873922 (Reactome)
p-STAT1(Y701) bound to p-IFNGR1R-HSA-909552 (Reactome)
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