Interferons (IFNs) are pleiotropic cytokines that mediate anti-viral responses,
inhibit proliferation and participate in immune surveillance and tumor suppression by
inducing the transcription of a number of IFN-stimulated genes. The IFN family includes
two main classes of related cytokines, type I IFNs and type II IFN. There are many type I
IFNs: interferon-alpha, interferon-beta and many others. By contrast, there is only one
type II IFN, interferon-gamma (IFN-gamma) that is produced
by activated T cells and natural killer (NK) cells .
IFN-gamma exerts its effects on cells by interacting
with the specific IFN-gamma receptor that is composed of two
subunits, IFNGR1 and IFNGR2. IFN-gamma receptor is expressed
on surfaces of nearly all cells. Binding of IFN-gamma to its
receptor induces oligomerization of the receptor and activation, via
trans-phosphorylation, of the receptor-associated Janus kinases 1 and 2
(JAK1 and JAK2). The activated
JAKs phosphorylate the intracellular domain of the receptor (e.g., tyrosine 440 of human
IFNGR1) that serves as a docking site for Signal transducer and activator of
transcription 1 (STAT1). STAT1
is phosphorylated on tyrosine 701, undergoes dimerization, translocates to the nucleus
and regulates gene expression by binding to gamma-activated sequence (GAS) elements in
the promoters of IFN-gamma-regulated genes .
Some kinases can phosphorylate STAT1 at serine 727
(Ser727). This phosphorylation is not required for STAT1
translocation to the nucleus or for its binding to the promoters. However, it is
essential for the full transcriptional activation. These kinases include Protein kinase C
delta (PKC-delta) and Calcium/calmodulin-dependent protein
kinase II (CaMK II) , .
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 . Although the
mechanism of PI3K-dependent PKC-delta activation is unclear,
PI3K-dependent phosphorylation of
PKC-delta by 3-Phosphoinositide dependent protein
kinase-1 (PDK (PDPK1)) was
Also IFN-gamma induces c-Cbl
mediated activation of v-CRK avian sarcoma virus CT10
oncogene homolog-like (CrkL). This provides a link between
the IFN-gamma receptor and the
Rap guanine nucleotide exchange factor 1 (C3G) and results
in the IFN-gamma-dependent activation of RAP1A, member of
RAS oncogene family (Rap1A), a protein known to exhibit
tumor suppressor activity and mediate growth inhibitory responses .
IFN-gamma also induces phosphorylation of Phospholipase C
gamma 2 (PLC-gamma 2) by
JAK1/2. Diacylglycerol (DAG) is
the product of the enzymatic activity of the PLC-gamma 2. It
can activate some of the protein kinase C isoforms of, including
PKC-alpha. The PKC-alpha can
stimulate tyrosine-protein kinase SRC-1
(c-Src) activity. Although
PKC-alpha can phosphorylate the
c-Src directly, Actin filament associated protein
(AFAP) is essential for this
c-Src activation .
c-Src in its turn activates
STAT1 by phosphorylation on
tyrosine 701. This IFN-gamma-induced PLC-gamma 2/
STAT1 pathway leads to the expression of Intercellular
adhesion molecule 1 (ICAM-1) gene .
There are many known STAT1-targets in IFN-gamma-mediated
signaling. These are SMAD family member 7 (SMAD7),
Interferon regulatory factor 1 (IRF1) and proteins involved
in cell cycle regulation, e.g., v-Myc myelocytomatosis viral oncogene homolog
(c-Myc) and Cyclin-dependent kinase inhibitor 1A
(p21) , .
IRF1 participates in the activation of the Suppressor of
cytokine signaling-1 (SOCS-1). The
SOCS-1 protein is critical for inhibiting
IFN-gamma responses .
IFN-gamma induces expression of
SOCS1 indirectly, by inducing
the expression of the IRF-1 transcription factor
via STAT1. IRF-1 in turn
stimulates transcription of the SOCS-1 gene .
Several proteins interact with STAT1 and modulate its
transcriptional activity: CREB-binding proteins (CBP and
p300), Minichromosome maintenance protein 5
(MCM5) and Breast cancer susceptibility gene 1
(BRCA1). CBP and
p300 possess histone acetyl transferase activity and
function as co-activators. MCM5 and
BRCA1 associate with phosphorylated
STAT1 and enhance its transcriptional activity .
In addition, IFN-gamma may activate JAK-STAT-independent
Calcium-dependent tyrosine kinase PTK2B protein tyrosine kinase 2 beta
(Pyk2(FAK2)) is a substrate for
JAK2. Pyk2(FAK2) phosphorylates
Mitogen-activated protein kinase kinase kinase 4 (MEKK4).
Phosphorylated MEKK4 in turn phosphorylates
Mitogen-activated protein kinase kinase 6 (MEK6).
Subsequently, MEK6 phosphorylates p38
MAPK that phosphorylates and activates Activating transcription factor 2
(ATF-2). Protein-tyrosine phosphatase 2C
(SHP-2) regulates this signaling pathway by
dephosphorylating MEKK4 and its activating kinase,
Another pathway stimulated by IFN-gamma involves
Mitogen-activated protein kinase 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/enhancer binding protein beta
(C/EBP-beta) and C/EBP-beta-driven expression
of Interferon regulatory factor 9 (IRF9) gene.
IRF9 is a subunit of ISGF3
transcription complex that participates in interferon signaling .
- Platanias LC
Mechanisms of type-I- and type-II-interferon-mediated signalling.
Nature reviews. Immunology 2005 May;5(5):375-86
- Ramana CV, Gil MP, Schreiber RD, Stark GR
Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling.
Trends in immunology 2002 Feb;23(2):96-101
- DeVries TA, Kalkofen RL, Matassa AA, Reyland ME
Protein kinase Cdelta regulates apoptosis via activation of STAT1.
The Journal of biological chemistry 2004 Oct 29;279(44):45603-12
- 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.
Proceedings of the National Academy of Sciences of the United States of America 2002 Apr 30;99(9):5971-6
- Deb DK, Sassano A, Lekmine F, Majchrzak B, Verma A, Kambhampati S, Uddin S, Rahman A, Fish EN, Platanias LC
Activation of protein kinase C delta by IFN-gamma.
Journal of immunology (Baltimore, Md. : 1950) 2003 Jul 1;171(1):267-73
- Belham C, Wu S, Avruch J
Intracellular signalling: PDK1--a kinase at the hub of things.
Current biology : CB 1999 Feb 11;9(3):R93-6
- Alsayed Y, Uddin S, Ahmad S, Majchrzak B, Druker BJ, Fish EN, Platanias LC
IFN-gamma activates the C3G/Rap1 signaling pathway.
Journal of immunology (Baltimore, Md. : 1950) 2000 Feb 15;164(4):1800-6
- Chang YJ, Holtzman MJ, Chen CC
Differential role of Janus family kinases (JAKs) in interferon-gamma-induced lung epithelial ICAM-1 expression: involving protein interactions between JAKs, phospholipase Cgamma, c-Src, and STAT1.
Molecular pharmacology 2004 Mar;65(3):589-98
- Gatesman A, Walker VG, Baisden JM, Weed SA, Flynn DC
Protein kinase Calpha activates c-Src and induces podosome formation via AFAP-110.
Molecular and cellular biology 2004 Sep;24(17):7578-97
- Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR
Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.
The EMBO journal 2000 Jan 17;19(2):263-72
- Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY
Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1.
Science (New York, N.Y.) 1996 May 3;272(5262):719-22
- Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM, Kay TW, Nicola NA, Hertzog PJ, Metcalf D, Hilton DJ
SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.
Cell 1999 Sep 3;98(5):597-608
- Saito H, Morita Y, Fujimoto M, Narazaki M, Naka T, Kishimoto T
IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-gamma.
Journal of immunology (Baltimore, Md. : 1950) 2000 Jun 1;164(11):5833-43
- Halfter UM, Derbyshire ZE, Vaillancourt RR
Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes.
The Biochemical journal 2005 May 15;388(Pt 1):17-28
- Roy SK, Hu J, Meng Q, Xia Y, Shapiro PS, Reddy SP, Platanias LC, Lindner DJ, Johnson PF, Pritchard C, Pages G, Pouyssegur J, Kalvakolanu DV
MEKK1 plays a critical role in activating the transcription factor C/EBP-beta-dependent gene expression in response to IFN-gamma.
Proceedings of the National Academy of Sciences of the United States of America 2002 Jun 11;99(12):7945-50