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Immune response  IFN gamma signaling pathway

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Immune response IFN gamma signaling pathway

Interferon-gamma signaling

Interferons (IFNs) are pleiotropic cytokines that mediate anti-viral responses,inhibit proliferation and participate in immune surveillance and tumor suppression byinducing the transcription of a number of IFN-stimulated genes. The IFN family includestwo main classes of related cytokines, type I IFNs and type II IFN. There are many type IIFNs: interferon-alpha, interferon-beta and many others. By contrast, there is only onetype II IFN, interferon-gamma ( IFN-gamma ) that is produced by activated T cellsand natural killer (NK) cells [1].

IFN-gamma exerts its effects on cells by interacting with the specificIFN-gamma receptor that is composed of two subunits, IFNGR1 and IFNGR2.IFN-gamma receptor is expressed on surfaces of nearly all cells. Binding ofIFN-gamma to its receptor induces oligomerization of the receptor and activation,via trans-phosphorylation, of the receptor-associated Janus kinases 1 and 2 ( JAK1and JAK2 ). The activated JAKs phosphorylate the intracellular domain of thereceptor (e.g., tyrosine 440 of human IFNGR1) that serves as a docking site for Signaltransducer and activator of transcription 1 ( STAT1 ) . STAT1 isphosphorylated on tyrosine 701, undergoes dimerization, translocates to the nucleus andregulates gene expression by binding to gamma-activated sequence (GAS) elements in thepromoters of IFN-gamma-regulated genes [2].

Some kinases can phosphorylate STAT1 at serine 727 (Ser727). Thisphosphorylation is not required for STAT1 translocation to the nucleus or for itsbinding to the promoters. However, it is essential for the full transcriptionalactivation. These kinases include Protein kinase C delta ( PKC-delta ) andCalcium/calmodulin-dependent protein kinase II ( CaMK II ) [3],[4].

Precise mechanisms of IFN-gamma-induced activation of these kinases are not clear.However, it was shown that IFN-gamma activates Phosphatidylinositol 3-kinase(PI3K)/ v-AKT murine thymoma viral oncogene homolog ( AKT ) signaling pathway,perhaps via the adapter Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl ) that binds regulatory subunit of PI3K (PI3K reg class 1A).PKC-delta is an effector of the PI3K pathway [5]. Although themechanism of PI3K-dependent PKC-delta activation is unclear, PI3K-dependentphosphorylation of PKC-delta by 3-Phosphoinositide dependent protein kinase-1 (PDK (PDPK1) ) was demonstrated [6].

Also IFN-gamma induces c-Cbl mediated activation of v-CRK avian sarcomavirus CT10 oncogene homolog-like (CrkL). This provides a link between theIFN-gamma receptor and the Rap guanine nucleotide exchange factor 1 (C3G ) and results in the IFN-gamma -dependent activation of RAP1A, memberof RAS oncogene family ( Rap1A ), a protein known to exhibit tumor suppressoractivity and mediate growth inhibitory responses [7].

IFN-gamma also induces phosphorylation of Phospholipase C gamma 2 (PLC-gamma 2 ) by JAK1/2. Diacylglycerol ( DAG ) is the product ofthe enzymatic activity of the PLC-gamma 2. It can activate some of the proteinkinase C isoforms of, including PKC-alpha. The PKC-alpha can stimulatetyrosine-protein kinase SRC-1 ( c-Src ) activity. Although PKC-alpha canphosphorylate the c-Src directly, Actin filament associated protein ( AFAP) is essential for this c-Src activation [8]. c-Src in itsturn activates STAT1 by phosphorylation on tyrosine 701. This IFN-gamma-inducedPLC-gamma 2/ PKC-alpha/ c-Src/ STAT1 pathway leads to theexpression of Intercellular adhesion molecule 1 ( ICAM-1 ) gene [9].

There are many known STAT1 -targets in IFN-gamma-mediated signaling. These areSMAD family member 7 ( SMAD7 ), Interferon regulatory factor 1 ( IRF1 ) andproteins involved in cell cycle regulation, e.g., v-Myc myelocytomatosis viral oncogenehomolog ( c-Myc ) and Cyclin-dependent kinase inhibitor 1A ( p21 ) [10], [11].

IRF1 participates in the activation of the Suppressor of cytokine signaling-1 (SOCS-1 ). The SOCS-1 protein is critical for inhibiting IFN-gammaresponses [12]. IFN-gamma induces expression of SOCS1indirectly, by inducing the expression of the IRF-1 transcription factor viaSTAT1. IRF-1 in turn stimulates transcription of the SOCS-1 gene[13].

Several proteins interact with STAT1 and modulate its transcriptional activity:CREB-binding proteins ( CBP and p300 ), Minichromosome maintenance protein5 ( MCM5 ) and Breast cancer susceptibility gene 1 ( BRCA1 ). CBPand p300 possess histone acetyl transferase activity and function asco-activators. MCM5 and BRCA1 associate with phosphorylated STAT1and enhance its transcriptional activity [2].

In addition, IFN-gamma may activate JAK-STAT-independent pathways.

Calcium-dependent tyrosine kinase PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2) ) is a substrate for JAK2. Pyk2(FAK2) phosphorylatesMitogen-activated protein kinase kinase kinase 4 ( MEKK4 ). PhosphorylatedMEKK4 in turn phosphorylates Mitogen-activated protein kinase kinase 6 (MEK6 ). Subsequently, MEK6 phosphorylates p38 MAPK thatphosphorylates and activates Activating transcription factor 2 ( ATF-2 ).Protein-tyrosine phosphatase 2C ( SHP-2 ) regulates this signaling pathway bydephosphorylating MEKK4 and its activating kinase, Pyk2(FAK2) [14].

Another pathway stimulated by IFN-gamma involves Mitogen-activated proteinkinase kinase kinase 1 ( MEKK1 ), Mitogen-activated protein kinase kinase 1 (MEK1 ) and Mitogen-activated protein kinases 1 and 3 ( ERK1/2 ).MEKK1/ MEK1/ ERK1/2 cascade regulates activity of CCAAT/enhancerbinding protein beta ( C/EBP-beta ) and C/EBP-beta-driven expression of Interferonregulatory factor 9 ( IRF9 ) gene. IRF9 is a subunit of ISGF3transcription complex that participates in interferon signaling [15].