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.Original Pathway at Reactome:

Ontology Tags



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  6. 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
  7. Shuai K, Stark GR, Kerr IM, Darnell JE Jr.; ''A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma.''; PubMed
  8. Argetsinger LS, Stuckey JA, Robertson SA, Koleva RI, Cline JM, Marto JA, Myers MG Jr, Carter-Su C.; ''Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity.''; PubMed
  9. 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
  10. Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE.; ''Three-dimensional structure of recombinant human interferon-gamma.''; PubMed
  11. 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
  12. Gough DJ, Levy DE, Johnstone RW, Clarke CJ.; ''IFNgamma signaling-does it mean JAK-STAT?''; PubMed
  13. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr.; ''Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions.''; PubMed
  14. Aaronson DS, Horvath CM.; ''A road map for those who don't know JAK-STAT.''; PubMed
  15. Decker T, Lew DJ, Mirkovitch J, Darnell JE Jr.; ''Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor.''; PubMed
  16. 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
  17. Nair JS, DaFonseca CJ, Tjernberg A, Sun W, Darnell JE Jr, Chait BT, Zhang JJ.; ''Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma.''; PubMed
  18. 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
  19. 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
  20. Ouellet S, Müller E, Rola-Pleszczynski M.; ''IFN-gamma up-regulates platelet-activating factor receptor gene expression in human monocytes.''; PubMed
  21. Wenta N, Strauss H, Meyer S, Vinkemeier U.; ''Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations.''; PubMed
  22. 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
  23. Palvimo JJ.; ''PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription.''; PubMed
  24. 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
  25. Schroder K, Hertzog PJ, Ravasi T, Hume DA.; ''Interferon-gamma: an overview of signals, mechanisms and functions.''; PubMed
  26. 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
  27. Matsuda T, Feng J, Witthuhn BA, Sekine Y, Ihle JN.; ''Determination of the transphosphorylation sites of Jak2 kinase.''; PubMed
  28. Shuai K, Schindler C, Prezioso VR, Darnell JE Jr.; ''Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.''; PubMed
  29. Strehlow I, Decker T.; ''Transcriptional induction of IFN-gamma-responsive genes is modulated by DNA surrounding the interferon stimulation response element.''; PubMed
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  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. Boehm U, Klamp T, Groot M, Howard JC.; ''Cellular responses to interferon-gamma.''; PubMed
  38. 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
  39. Pearse RN, Feinman R, Shuai K, Darnell JE Jr, 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
  40. 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
  41. 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
  42. DeVries TA, Kalkofen RL, Matassa AA, Reyland ME.; ''Protein kinase Cdelta regulates apoptosis via activation of STAT1.''; PubMed
  43. Bach EA, Aguet M, Schreiber RD.; ''The IFN gamma receptor: a paradigm for cytokine receptor signaling.''; PubMed
  44. 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
  45. Mowen K, David M.; ''Regulation of STAT1 nuclear export by Jak1.''; PubMed
  46. McBride KM, Reich NC.; ''The ins and outs of STAT1 nuclear transport.''; PubMed
  47. 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
  48. 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


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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
HLA class II

histocompatibility antigen, DP [plasma

ProteinP04440 (Uniprot-TrEMBL)
FCGRAProteinREACT_26475 (Reactome)
IFNG [extracellular region]ProteinP01579 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DRB1-7 beta chain [plasma

ProteinP13761 (Uniprot-TrEMBL)
IFNGR1:JAK1:INFG2:JAK2ComplexREACT_25803 (Reactome)
IRF 1-9ProteinREACT_26465 (Reactome)
IFNGR1 [plasma membrane]ProteinP15260 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DRB1-10 beta chain [plasma

ProteinQ30167 (Uniprot-TrEMBL)
JAK1 [cytosol]ProteinP23458 (Uniprot-TrEMBL)
GAS promoter region

in IFNG-regulated

REACT_26763 (Reactome)
IFNGR2 [plasma membrane]ProteinP38484 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
JAK2 [cytosol]ProteinO60674 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DP alpha chain precursor

[plasma membrane]
ProteinP20036 (Uniprot-TrEMBL)
IFNG:IFNGR1:JAK1:IFNGR2:JAK2ComplexREACT_25865 (Reactome)
HLA class II

histocompatibility antigen, DR beta 4 chain [plasma

ProteinP13762 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
HLA class II

histocompatibility antigen, DRB1-14 beta chain [plasma

ProteinQ9GIY3 (Uniprot-TrEMBL)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2ComplexREACT_26738 (Reactome)
IFNG homodimerComplexREACT_26955 (Reactome)
p-Y1007-JAK2 [cytosol]ProteinO60674 (Uniprot-TrEMBL)
GBPProteinREACT_26189 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
PTAFRProteinP25105 (Uniprot-TrEMBL)
IFNG:IFNGR1:p-JAK1:IFNGR2:p-JAK2ComplexREACT_26286 (Reactome)
IFN-gamma upregulated CAMsProteinREACT_26072 (Reactome)
p-Y-JAK1 [cytosol]ProteinP23458 (Uniprot-TrEMBL)
IFI30(69-243)ProteinP13284 (Uniprot-TrEMBL)
IFNG:p-IFNGR1:p-JAK1:IFNGR2:p-JAK2ComplexREACT_25650 (Reactome)
HLA class II

histocompatibility antigen, DQ [plasma

ProteinP01909 (Uniprot-TrEMBL)
p-Y440-IFNGR1 [plasma membrane]ProteinP15260 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DQ beta 2 chain [plasma

ProteinP05538 (Uniprot-TrEMBL)
STAT1-1ProteinP42224-1 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DR-1 beta chain precursor

[plasma membrane]
ProteinP01912 (Uniprot-TrEMBL)
STAT1 bound to p-IFNGR1ComplexREACT_26587 (Reactome)
HLA class II

histocompatibility antigen, DRB1-12 beta chain [plasma

ProteinQ95IE3 (Uniprot-TrEMBL)
STAT1-1 [cytosol]ProteinP42224-1 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DRB1-16 beta chain [plasma

ProteinQ29974 (Uniprot-TrEMBL)
p-STAT1(Y701) bound to p-IFNGR1ComplexREACT_26108 (Reactome)
HLA class II

histocompatibility antigen, DRB1-9 beta chain precursor

[plasma membrane]
ProteinQ9TQE0 (Uniprot-TrEMBL)
p-Y701-STAT1-1 [cytosol]ProteinP42224-1 (Uniprot-TrEMBL)
PTPN2-1ProteinP17706-2 (Uniprot-TrEMBL)
IFNG-activated factor (GAF)ComplexREACT_26637 (Reactome)
GAF bound to GAS promoter elementComplexREACT_25470 (Reactome)
p-S727,Y701-STAT1-1 [cytosol]ProteinP42224-1 (Uniprot-TrEMBL)
CIITAProteinP33076 (Uniprot-TrEMBL)
IFNG-activated factor (GAF)ComplexREACT_26144 (Reactome)
Class I MHC heavy chain (MHC HC)ProteinREACT_26784 (Reactome)
p-S727,Y701-STAT1-1 [nucleoplasm]ProteinP42224-1 (Uniprot-TrEMBL)
MT2AProteinP02795 (Uniprot-TrEMBL)
IFNG:IFNGR1:JAK1:IFNGR2:p-JAK2:SOCS-1/-3ComplexREACT_26775 (Reactome)
OAS proteinsProteinREACT_26755 (Reactome)
SOCS1 [cytosol]ProteinO15524 (Uniprot-TrEMBL)
B2M(21-119)ProteinP61769 (Uniprot-TrEMBL)
SOCS3 [cytosol]ProteinO14543 (Uniprot-TrEMBL)
SP100ProteinP23497 (Uniprot-TrEMBL)
SOCS-1 and SOCS-3ProteinREACT_25587 (Reactome)
MHC class II alpha/beta dimerComplexREACT_121884 (Reactome)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DQ [plasma

ProteinP01906 (Uniprot-TrEMBL)
PIAS1ProteinO75925 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DR alpha chain precursor

[plasma membrane]
ProteinP01903 (Uniprot-TrEMBL)
SUMO1ProteinP63165 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DQ [plasma

ProteinP01920 (Uniprot-TrEMBL)
p-STAT1 dimer:PIAS:SUMO1ComplexREACT_25840 (Reactome)
HLA class II

histocompatibility antigen, DQB1*0602 beta chain precursor

[plasma membrane]
ProteinP01920 (Uniprot-TrEMBL)
PIAS1 [nucleoplasm]ProteinO75925 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DR beta 5 chain [plasma

ProteinQ30154 (Uniprot-TrEMBL)
SUMO1 [nucleoplasm]ProteinP63165 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DRB1-1 beta chain [plasma

ProteinP04229 (Uniprot-TrEMBL)
p-STAT1 dimer bound to p-IFNGR1ComplexREACT_25936 (Reactome)
HLA class II

histocompatibility antigen, DRB1-11 beta chain [plasma

ProteinP20039 (Uniprot-TrEMBL)
CaMKII and PKC-deltaProteinREACT_26704 (Reactome)
HLA class II

histocompatibility antigen, DRB1-13 beta chain [plasma

ProteinQ5Y7A7 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
HLA class II

histocompatibility antigen, DRB1-15 beta chain [plasma

ProteinP01911 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HLA class II

histocompatibility antigen, DRB1-4 beta chain [plasma

ProteinP13760 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
HLA class II

histocompatibility antigen, DRB1-8 beta chain [plasma

ProteinQ30134 (Uniprot-TrEMBL)
PTPs-SHP1/2/PTP1BProteinREACT_26675 (Reactome)
HLA class II

histocompatibility antigen, DRB3-1 beta chain precursor

[plasma membrane]
ProteinP79483 (Uniprot-TrEMBL)
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