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.
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Aaronson DS, Horvath CM.; ''A road map for those who don't know JAK-STAT.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Strehlow I, Decker T.; ''Transcriptional induction of IFN-gamma-responsive genes is modulated by DNA surrounding the interferon stimulation response element.''; PubMedEurope PMCScholia
McBride KM, Reich NC.; ''The ins and outs of STAT1 nuclear transport.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Bach EA, Aguet M, Schreiber RD.; ''The IFN gamma receptor: a paradigm for cytokine receptor signaling.''; PubMedEurope PMCScholia
Ouellet S, Müller E, Rola-Pleszczynski M.; ''IFN-gamma up-regulates platelet-activating factor receptor gene expression in human monocytes.''; PubMedEurope PMCScholia
Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE.; ''Three-dimensional structure of recombinant human interferon-gamma.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Stratowa C, Audette M.; ''Transcriptional regulation of the human intercellular adhesion molecule-1 gene: a short overview.''; PubMedEurope PMCScholia
Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Jänne OA, Palvimo JJ, Silvennoinen O.; ''PIAS proteins promote SUMO-1 conjugation to STAT1.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Matsuda T, Feng J, Witthuhn BA, Sekine Y, Ihle JN.; ''Determination of the transphosphorylation sites of Jak2 kinase.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Huang F, Xiao H, Sun BL, Yang RG.; ''Characterization of TRIM62 as a RING finger E3 ubiquitin ligase and its subcellular localization.''; PubMedEurope PMCScholia
Gough DJ, Levy DE, Johnstone RW, Clarke CJ.; ''IFNgamma signaling-does it mean JAK-STAT?''; PubMedEurope PMCScholia
Shuai K, Stark GR, Kerr IM, Darnell JE.; ''A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma.''; PubMedEurope PMCScholia
Wenta N, Strauss H, Meyer S, Vinkemeier U.; ''Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations.''; PubMedEurope PMCScholia
Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S.; ''Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Fountoulakis M, Zulauf M, Lustig A, Garotta G.; ''Stoichiometry of interaction between interferon gamma and its receptor.''; PubMedEurope PMCScholia
Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K.; ''Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050.''; PubMedEurope PMCScholia
Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.; ''Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kaplan DH, Greenlund AC, Tanner JW, Shaw AS, Schreiber RD.; ''Identification of an interferon-gamma receptor alpha chain sequence required for JAK-1 binding.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Decker T, Lew DJ, Mirkovitch J, Darnell JE.; ''Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor.''; PubMedEurope PMCScholia
Palvimo JJ.; ''PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Boehm U, Klamp T, Groot M, Howard JC.; ''Cellular responses to interferon-gamma.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ozato K, Shin DM, Chang TH, Morse HC.; ''TRIM family proteins and their emerging roles in innate immunity.''; PubMedEurope PMCScholia
DeVries TA, Kalkofen RL, Matassa AA, Reyland ME.; ''Protein kinase Cdelta regulates apoptosis via activation of STAT1.''; PubMedEurope PMCScholia
Rajsbaum R, Stoye JP, O'Garra A.; ''Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells.''; PubMedEurope PMCScholia
Greenlund AC, Farrar MA, Viviano BL, Schreiber RD.; ''Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91).''; PubMedEurope PMCScholia
Shuai K, Schindler C, Prezioso VR, Darnell JE.; ''Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.''; PubMedEurope PMCScholia
Schroder K, Hertzog PJ, Ravasi T, Hume DA.; ''Interferon-gamma: an overview of signals, mechanisms and functions.''; PubMedEurope PMCScholia
Argetsinger LS, Kouadio JL, Steen H, Stensballe A, Jensen ON, Carter-Su C.; ''Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Clark JD, Flanagan ME, Telliez JB.; ''Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.''; PubMedEurope PMCScholia
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
with GAS promoter
elementsAnnotated Interactions
with GAS promoter
elementswith GAS promoter
elementsIFNG 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.