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Molecular Immunology 44 (2007) 2497–2506
Review
Cytokine receptor signaling through the Jak–Stat–Socs
pathway in disease
Lynda A. O’Sullivan, Clifford Liongue, Rowena S. Lewis,
Sarah E.M. Stephenson, Alister C. Ward ∗
School of Life & Environmental Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia
Received 28 October 2006; received in revised form 21 November 2006; accepted 22 November 2006
Available online 17 January 2007
Abstract
The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors
are one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding of
the cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs),
focussing on their contribution to diseases of an immune or hematologic nature.
© 2006 Elsevier Ltd. All rights reserved.
Keywords: Cytokine receptor; Jak–Stat–Socs; Inflammatory diseases
1. Introduction
The complexity of multicellular organisms is due to the evolution of systems enabling cells to respond to distinct cues.
Cytokines and their specific receptors represent one such system that plays a key role in blood and immune cells (Sato
and Miyajima, 1994). Signaling via the largest cytokine receptor family, the hematopoietin receptors, involves binding of a
cytokine to a specific receptor chain to initiate formation of a
functional cytokine receptor complex (Kishimoto et al., 1994)
(Fig. 1). Hematopoietin receptors lack intrinsic tyrosine kinase
activity and instead rely on cytoplasmic kinases, such as Jaks, to
initiate intracellular signaling (Remy et al., 1999). The Jak proteins then phosphorylate tyrosine residues within the receptor
chains, creating docking sites for dormant cytoplasmic proteins,
particularly the Stats. These dimerize and translocate to the
nucleus, where they function as transcription factors to regulate gene expression (Ward et al., 2000). These target genes
include the Socs genes, whose encoded proteins generally act
in a negative feedback loop to suppress further signaling. This
review provides an overview of our current understanding of
hematopoietin receptors, Janus kinases (Jaks), Signal transduc∗
Corresponding author. Tel.: +61 3 9244 6708; fax: +61 3 9251 7328.
E-mail address: [email protected] (A.C. Ward).
0161-5890/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.molimm.2006.11.025
ers and activators of transcription (Stats) and Suppressors of
cytokine signaling (Socs) and their role in immune and hematologic disease.
2. Cytokine receptors
Hematopoietin receptors possess a conserved extracellular region, known as the cytokine receptor homology domain
(CHD) (Uze et al., 1995), along with a range of other structural
modules, including extracellular immunoglobulin (Ig)-like and
fibronectin type III (FBNIII)-like domains, a transmembrane
domain, and intracellular homology domains (Bazan, 1990;
Kishimoto et al., 1994). Hematopoietin receptors are divided
into two classes, which have divergent CHDs (Bazan, 1990).
2.1. Class I receptors
Class I cytokine receptors are characterized by two pairs of
conserved cysteines linked via disulfide bonds and a C-terminal
WSXWS motif within their CHD (Bazan, 1990). Class I receptors fall into three major families, IL-2R, IL-3R and IL-6R, as
determined by usage of shared receptor chains (Table 1). Each
receptor complex consists of at least one signal transducing
receptor chain containing membrane-proximal Box 1 and Box
2 motifs associated with Jak docking (Leonard and Lin, 2000).
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The IL-3R family is primarily involved in the production of
myelomonocytic cells. For example, IL-3R signaling is involved
in the differentiation of pluripotent stem cells into various
myeloid progenitor cells (Mangi and Newland, 1999), while IL5 is involved in eosinophil development (Roboz and Rafii, 1999).
Fig. 1. Activation of the Jak–Stat–Socs pathway by cytokine receptors.
Cytokines bind to specific cell surface receptors chains, which lead to receptor complex formation and the activation of one or more associated Jaks. These
phosphorylate the intracellular tyrosines of the receptor complex, creating docking sites for Stats, which themselves become tyrosine-phosphorylated forming
homo- or heterodimeric complexes that translocate to the nucleus. Here they bind
to specific gene promoters to activate transcription of a range of target genes. Socs
genes are activated by cytokine receptor signaling via the Jak–Stat pathway. The
encoded proteins then act to negatively regulate cytokine signaling in a negative
feedback loop by three distinct mechanisms: kinase inhibition (of Jaks), bindingsite competition (of Stats) and degradation (of receptor complexes) (modified
from Ward et al., 2000).
2.1.1. The IL-2R family
This family predominantly utilizes the common receptor
chain, IL-2R␥c , along with a single ligand-specific receptor
chain (Ozaki and Leonard, 2002). However, IL-4R␣ and IL7R␣ also form additional receptor complexes with other receptor
chains (Ozaki and Leonard, 2002), whilst IL-2R␣ and IL-15R␣
chains are not hematopoietin receptors, but instead contain distinctive ‘sushi domain’ structures (Leonard and Lin, 2000).
Members of the IL-2R family associate with Jak1 and Jak3,
primarily activating Stat5, although certain family members can
also activate Stat1, Stat3, or Stat6 (Gaffen, 2001; Roy et al.,
2002).
The IL-2R family is primarily involved in the growth and
maturation of lymphoid cells (Gaffen, 2001; Parrish-Novak
et al., 2000). For example, the archetypical IL-2R has a
range of functions including proliferation of T cells and other
immunoregulatory roles (Gaffen, 2001). Similarly, IL-7R is
involved in the development of T cells as well as T cell homeostasis (Fry and Mackall, 2005), IL-4R signaling promotes T helper 2
(TH 2) cell development (Paul, 1997), while IL-21R is involved
in natural killer (NK) cell proliferation and the regulation of
inflammation (Parrish-Novak et al., 2000).
2.1.2. The IL-3R family
This family shares the common signal transducer chain IL3R␤c in combination with specific chains (Boulay et al., 2003;
Ozaki and Leonard, 2002). IL-3R␤c is associated with Jak2 and
signals primarily via Stat5, although activation of other Stats
has been observed in certain cell lines (de Groot et al., 1998).
2.1.3. The IL-6R family
The core IL-6R family members employ the shared receptor subunits glycoprotein 130 (GP130), with many also using
the leukemia inhibitory factor receptor chain (LIFR). GP130
associates with Jak1, Jak2, and tyrosine kinase 2 (Tyk2), which
activate Stat1, Stat3 and Stat5 (Heinrich et al., 1998). The IL-12R
subfamily consists of complexes containing the shared receptors, IL-12p40 and IL-12R␤1 , along with the specific IL-12R␤2
or IL-23R␣ chain. These activate more specific downstream
components: for example, IL-12R specifically activates Stat4,
while IL-23R activates Stat3 (Watford et al., 2004). Unlike other
members of the IL-6R family, granulocyte colony-stimulating
factor receptor (G-CSFR) and obesity gene receptor (OBR)
form homodimers (Devos et al., 1997; Hiraoka et al., 1994),
but activate similar Jaks and Stats to GP130.
The essential role of the GP130 and LIFR subunits is highlighted by the lethality of the respective knockout mice (Ware et
al., 1995; Yoshida et al., 1996). Individual receptor complexes
have more specific roles: ciliary neurotrophic factor receptor
(CNTFR) promotes survival and differentiation of cells within
the nervous system (Elson et al., 2000), IL-6R mediates immune,
hematopoietic, and thrombopoietic responses (Ito, 2003). The
IL-12R family functions in innate immunity (Watford et al.,
2004), while the G-CSFR plays a key role in granulocytic development (Lieschke et al., 1994), and OBR is involved in appetite
control (Tartaglia et al., 1995).
2.1.4. Homomeric receptors
The erythropoietin receptor (EPOR), thrombopoietin receptor (TPOR), prolactin receptor (PRLR), and growth hormone
receptor (GHR) form homodimers in the presence of their
respective ligands (Heldin, 1995), and associate exclusively with
Jak2 and signal via Stat5 (Boulay et al., 2003). EPOR and TPOR
are mediators of erythroid (Richmond et al., 2005) and platelet
(Fishley and Alexander, 2004) production, respectively, GHR
mediates growth and sexual dimorphism (Frank, 2001), while
PRLR is involved in mammary development and lactation (BoleFeysot et al., 1998).
2.2. Class II receptors
Class II hematopoietin receptors also have two pairs of cysteines but with a different arrangement to Class I and also lack
the WSXWS motif (Bazan, 1990). The dimerization paradigm
of the class II cytokine receptor complex entails a long intracellular ligand binding receptor and a short intracellular accessory
receptor. Only tissue factor (TF), a homodimer, and IL-22BP,
a decoy receptor, fail to observe this paradigm. The dimerization properties results in 10 receptor complexes formed from a
pool of 12 class II receptor chains (Kotenko and Langer, 2004)
(Table 2). Class II cytokine receptors are primarily involved in
Table 1
Structure and function of class I cytokine receptor complexes
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antiviral and inflammation modulation, apart from TF that is
involved in the blood clotting cascade.
2.2.1. Antiviral receptors
There are three receptor complexes that bind to interferons
(IFN) to confer antiviral activity, type I IFNR for IFN␣/␤/␬/␻/␧,
type II IFNR for IFN␥ and IFN␭R for IFN␭1–3 (Kotenko and
Langer, 2004). Both type I IFNR and IFN␭R have been shown to
induce antiviral activity, and signal via Jak2 and Tyk2 in a similar
Stat2-dependent downstream pathways (Kotenko et al., 2003).
Defects in type I IFN signaling, including a null IFN␣R1 mutation, results in immunocompromised mice that are susceptible to
viral infections (Hwang et al., 1995). Mice deficient in IFN␥R1
or IFN␥R2 display an increase in susceptibility to pathogenic
bacteria (Jeanmougin et al., 1998).
2.2.2. Non-antiviral receptors
There is extensive sharing of IL-10R2, IL-20R1, IL-20R2,
and IL-22R1 with the three cytokine specific receptor subunits,
IFN␭R1, IL-10R and IL-20R1, creating a total of six receptor complexes. These receptor complexes primarily associate
with Jak2 and Tyk2, whilst signaling via Stat1, Stat3 and Stat5
(Kotenko and Pestka, 2000). With the exception of IFN␭R1,
these receptor subunits modulate the inflammatory response
(Blumberg et al., 2001; Conti et al., 2003; Renauld, 2003).
3. The downstream Jak–Stat–Socs components
Table 2
Structure and function of class II cytokine receptor complexes
3.1. Jaks
Four Jaks have been identified in mammals: Jak1, Jak2,
Jak3 and Tyk2. Only Jak3 shows restricted expression,
being confined predominately to cells of hematopoietic origin
(Kawamura et al., 1994). Jaks posses an N-terminal Four-pointone/Ezrin/Radixin/Moesin (FERM) domain that appears to be
important for the interaction between Jaks and their cognate
cytokine receptor (Chen et al., 1997; Zhao et al., 1995), a central
Jak homology (JH) 2 pseudokinase domain that serves an essential regulatory role (Saharinen et al., 2000), and a C-terminal
JH1 kinase domain. In addition to signal transduction, Jak binding may promote cell surface expression of cytokine receptors
(Huang et al., 2001).
3.2. Stats
Seven Stat family members have been identified in mammals: Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b and Stat6. Each
is composed of five essential domains, including a four helix
bundle transactivation domain, a central ␤-barrel Ig-like DNA
binding domain, a helical linker domain, an SH2 domain and an
effector domain (Neculai et al., 2005). Stat specificity is largely
determined by the binding preference of their SH2 domains for
phosphorylated tyrosines on specific receptors, although cell
type and differentiation state also contributes. In addition, formation of heterodimers, tetramers and other higher order complexes
expands the range of Stat/DNA binding opportunities (Ward et
al., 2000).
L.A. O’Sullivan et al. / Molecular Immunology 44 (2007) 2497–2506
3.3. Socs
Eight mammalian Socs proteins have been identified:
Socs1–7 and cytokine-inducible SH2 protein (Cis). Members
of the Socs family of proteins possess three domains: an
N-terminal domain of variable length that is not well conserved between members and whose function remains largely
unknown; a central SH2 domain, required for interaction with
target phosphotyrosine residues; and a highly conserved Cterminal domain known as the Socs box, believed to be involved
in proteasomal targeting (Zhang et al., 1999). Socs proteins can
negatively regulate cytokine receptor signaling by several distinct mechanisms. Firstly, they can directly inhibit Jak kinases
by binding to the receptor or to the Jak activation loop (Endo
et al., 1997). Secondly, they can compete with other signaling molecules containing SH2-domains for binding sites on
the receptor (Matsumoto et al., 1997). Thirdly, they can target the receptor complex and associated signaling proteins for
proteasomal degradation through the Socs box, which mediates
interactions with elongins B and C to recruit an E3 ubiquitin
ligase complex (Hilton et al., 1998; Zhang et al., 1999).
4. The cytokine receptor-Jak–Stat–Socs pathway in
disease
Perturbation of cytokine receptor signaling has important
pathological consequences, particularly with respect to immune
and blood cells. These can affect the development or function of specific cell populations in either a positive or negative
manner. Therefore, immune and hematopoietic deficiencies are
observed, as well as excess production and/or activation of specific cell populations, including malignancy.
4.1. Severe combined immunodeficiency
The majority of cases of severe combined immune deficiency
(SCID) can be attributed to defects in signaling by members of
the IL-2R family (Buckley, 2004). The most common form of
the disease, termed X-linked SCID, is due to a mutation of the
IL-2R␥c gene (Kovanen and Leonard, 2004). Since IL-2R␥c is
the common signal transducer of the IL-2R family, this leads
to simultaneous perturbation of signaling for several cytokines,
and so patients suffer severe immune defects, manifested in the
total loss of T and NK cells (Buckley, 2004; Ozaki and Leonard,
2002). A phenotypically similar, but autosomal recessive form of
SCID, with a lack of T and NK cells and impaired mature B cell
function, is caused by mutations in Jak3, the main signal transducer for IL-2R␥c (Pesu et al., 2005). Finally, mutations of the
IL-7R␣ are associated with a milder form of SCID, characterized
by a specific lack of T cells (Buckley, 2004; Puel et al., 1998).
4.2. Other immunodeficiencies
Defects in class II receptor signaling components produce
more subtle and specific immune deficiencies. Nonsense mutations prior to the transmembrane domain of IFN␥RI results in
an absence of cell-surface expression leading to compromised
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immunity, particularly increased susceptibility to mycobacterial
infection and mortality (Jouanguy et al., 2000). Patients with
loss-of-function Stat1 (L706S) mutation are also susceptible to
mycobacterial infection (Dupuis et al., 2001), consistent with
the involvement of this Stat in both types I and II IFNR signaling. Finally, a spontaneously occurring murine Tyk2 mutant is
highly sensitive to Toxoplasma gondii infection, due to impaired
IL-12R responses (Shaw et al., 2003).
4.3. Inflammatory diseases
Several different inflammatory diseases have been shown to
be due to abnormalities in cytokine receptor signaling pathways,
principally in T cells. For example, in Crohn’s disease, an inflammatory disease of the colon and small intestine, constitutive
activation of both Stat3 and Stat5 have been observed specifically in the intestinal T cells (Lovato et al., 2003). Patients with
chronic obstructive pulmonary disease patients also show high
levels of activated Stat4, which correlate with an increase in lung
injury. In this case, it is thought to be due to excess IL-12R signaling, and that the hyperactivated Stat4 induces T cells toward the
TH 1 type, potentially damaging the lung tissue (Di Stefano et al.,
2004). Asthmatic patients also show activation of Stat1, which
also correlated with an increase in T cell accumulation (Sampath
et al., 1999). In addition, certain polymorphisms of Stat6 have
been linked to allergic diseases (Tamura et al., 2003). In support
of this, Stat6 knockout mice are resistant to certain inflammatory
conditions (Kuperman et al., 2002). Patients with TH 2 type diseases, such as atopic asthma and dermatitis also show a high level
of SOCS3 expression in peripheral T cells, which is tightly correlated with severity of disease (Seki et al., 2003). In contrast,
Socs1 has been implicated as an important negative regulator
of various inflammatory diseases including rheumatoid arthritis
(RA) and systemic lupus erythematosus (SLE) although this is
probably via its effects on IFN receptor signaling (Egan et al.,
2003; Ernst et al., 2001; Fujimoto et al., 2004).
4.4. Autoimmune disorders
A range of autoimmune disorders also involve dysregulated
signaling of several cytokine receptor types. For example, two
polymorphisms in the FERM domain of Tyk2 are associated
with decreased susceptibility to systemic autoimmune disease
(SLE) that is characterized by arthritis, skin rashes, nephritis,
and vasculitis among other symptoms (Sigurdsson et al., 2005).
This is believed to be due to a loss in Type I IFNR signaling,
which is supported in IfnαR deficient mice that show reduced
SLE disease and mortality (Santiago-Raber et al., 2003). In contrast, humans with allergic conjunctivitis showed a correlation
between the level of expression of Socs3 with the clinical, pathological and severity of the diseases (Ozaki et al., 2005; Seki et
al., 2003). A similar role for Socs5 has also been reported in a
mouse model of this disease (Ozaki et al., 2005), as well murine
experimental autoimmune uveitis, an autoimmune disease of the
retina (Takase et al., 2005). Peripheral blood mononuclear cells
from patients suffering from uveitis also have significantly elevated SOCS5 mRNA, but when given anti-IL-2R␣ therapy, the
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expression levels significantly reduced, suggesting this is due to
hyperactivated T cell signaling through the IL-2R (Egwuagu et
al., 2005).
4.5. Infectious disease pathogenesis
Cytokine signaling components are also specifically targeted
by infectious agents to facilitate infection. For example, measles
virus infection is augmented by suppression of type I IFNRinduced antiviral responses (Yokota et al., 2003). In contrast,
the Hepatitis C virus (HCV) protein NS5A interacts with and
activates Jak1, which in turn activates Stat3 and so contributes
to the progression of HCV related disease (Sarcar et al., 2004).
Finally, patients infected with HIV show reduced expression of
Stat5 in T cells (Pericle et al., 1998), but constitutive activation
of Stat proteins in other cells (Bovolenta et al., 1999).
4.6. Hematological defects
A range of haematological defects have been associated with
mutations in specific class I cytokine receptors. Thus, missense and truncating mutations of TPOR have been described
in patients with congenital megakaryocytic thrombocytopenia,
characterized by reduced platelet numbers in the blood (Fishley
and Alexander, 2004). Two classes of G-CSFR mutations have
been described in severe congenital neutropenia patients (Ward,
2007): extracellular mutants that lead to a hyporesponsiveness to
G-CSF therapy (Ward et al., 1999), as well as intracellular truncation mutants (Dong et al., 1995). Finally, mutations of IL-3R␤c
have been found in several pediatric pulmonary alveolar proteinosis patients, who show alveolar accumulation of phospholipids and proteins derived from surfactant proteins due in part to
defective alveolar macrophage function (Dirksen et al., 1997).
4.7. Myeloproliferative disorders
Other (hyperactivating) mutations affecting class I cytokine
receptor signaling pathway are found associated with several
myeloproliferative diseases. A missense mutation within the
transmembrane domain of TPOR leads to familial essential
thrombocythemia, a disorder characterized by elevated platelet
levels and megakaryocyte levels in the blood and bone marrow,
respectively (Fishley and Alexander, 2004), a polymorphism in
the intracellular domain of G-CSFR shows a strong association
with myelodysplastic syndromes (Wolfler et al., 2005), while
truncation of EPOR has been implicated in erythrocytosis, a
benign proliferative condition affecting red blood cells (de la
Chapelle et al., 1993). In addition, heterozygous and homozygous V617F mutations within the JH2 domain of Jak2 have
been identified in a high percentage of classical myeloproliferative disorders, including patients with polycythemia vera,
essential thrombocythemia and idiopathic myelofibrosis (Baxter
et al., 2005; James et al., 2005; Kralovics et al., 2005; Levine et
al., 2005), and at a lower frequency in other myeloproliferative
disorders (Steensma et al., 2005). These mutations result in constitutive tyrosine phosphorylation of Jak2, promoting cytokine
receptor hypersensitivity (James et al., 2005).
4.8. Leukemias/lymphomas
Inappropriate activation of class I cytokine receptor signaling also appears to be a hallmark of a range of malignancies,
including leukemias and lymphomas. For example, the IL-3R␣
chain is overexpressed in blast cells from >80% of acute myeloid
leukemia (AML) patients, leading to increased downstream
signaling, particularly of Stat5 (Testa et al., 2004). In other
AML patients, a truncated form of IL-3R␤c , IL-3R␤IT , is overexpressed and leads to a disruption of normal signaling (Gale
et al., 1998). Similarly, a C-terminally truncated version of GCSFR, also leading to hyperactivation of Stat5 (Gits et al., 2007),
is observed in a group of severe congenital neutropenia patients
predisposed to AML, while alternate G-CSFR mutations are
seen in cases of de novo AML (Touw and Dong, 1996).
A range of genetic changes leading to hyperactivation of
Jak2 are associated with leukemia. Three alternate translocations
have been identified between the transcription factor TEL/ETV6
and Jak2 in early pre-B acute lymphoid leukemia (ALL), atypical chronic myelomonocytic leukemia CML and T cell ALL
(Lacronique et al., 1997; Peeters et al., 1997). More recently,
a chimeric protein produced by a translocation of PCM1 with
Jak2 has also been identified in atypical CML (Bousquet et al.,
2005). In addition, Jak2 V617F mutations have been observed
in AML, CML and chronic neutrophilic leukemia (Steensma et
al., 2005), as well as a K607N mutation in AML (Lee et al.,
2006). Finally, amplification of genomic regions encompassing
the Jak2 gene has been seen in Hodgkin’s lymphoma patients
(Joos et al., 2000).
Constitutive activation of Stats is also a common observation
in malignancy. This includes Stat1 in AML, B cell ALL, erythroleukemia and Epstein-Barr virus related lymphomas (Ward
et al., 2000; Weber-Nordt et al., 1996), Stat3 in Hodgkins
Disease, AML and human T cell lymphoma virus (HTLV)
dependent T cell leukemia (Calo et al., 2003; Catlett-Falcone
et al., 1999; Dolled-Filhart et al., 2003; Hayakawa et al., 1998;
Lovato et al., 2003), and Stat5 in erythroleukemia, AML, CML,
ALL, megakaryocyte leukemia and HTLV dependent T cell
leukemia (Ward et al., 2000). It is also often triggered by
leukemic oncoproteins, which include Tel-Jak2 (Lin et al., 2000)
and Bcr-Abl (Shuai et al., 1996). Stat3 and Stat6 have been constitutively activated in Hodgkins Disease. In particular 78% of
the Reed-Sternberg cells of classical Hodgkin’s lymphoma show
constitutive Stat6 phosphorylation (Skinnider et al., 2002).
In contrast, Socs1 appears to act as a tumor suppressor. Thus,
methylation and subsequent inactivation of the SOCS1 gene has
been observed in a variety of human cancers, including around
60% of newly diagnosed AML (Chen et al., 2003). CML patients
also demonstrate SOCS1 methylation that reverts to an unmethylated state during remission (Liu et al., 2003).
5. Conclusions
The dissection of cytokine receptor signaling and the role of
its various components in health and disease point to some general conclusions. Firstly, many of the components have specific
relationships that mediate relatively narrow functions, espe-
L.A. O’Sullivan et al. / Molecular Immunology 44 (2007) 2497–2506
cially in immune or hematologic function. Thus, the IL-2R
family exclusively engages Jak3, Stat4 and Stat6 to assist in
the development of acquired immunity, while the IFNs almost
exclusively engage Tyk2, Stat1, Stat2 and Socs1 to mediate and
modulate antiviral and inflammatory responses. Another key
module appears to be the Jak2–Stat5–Cis pathway, although this
is employed via a diverse range of receptors, for example, by the
IL-3R family to produce and regulate cells of the innate immune
system, by EPOR to perform a similar role for red blood cells,
but also by PRLR and GHR, although the later recruits Socs2
as well. True pleiotropy is the exception, largely limited to IL6 receptor family, Jak2, Stat3, Socs1 and Socs3. In addition,
some components are involved in alternate paradigms, including TF, Socs6 and Socs7. Secondly, and somewhat related to
the first point, many mutations or perturbations of components
converge at the disease level. For example, mutations in several
of the IFN components lead to reduced response to infectious
disease. Enhanced signaling (mediated by hyperactive/receptor
mutations, activating Jak mutations, constitutive active Stats, or
suppression of Socs expression) can cause proliferative disorders, particularly of a hematological, or inflammatory nature.
However, this means there is considerable potential to develop
common disease therapeutics for such diseases and that multiple
targets can also be considered simultaneously.
Acknowledgements
LAO’S is a recipient of an Australian Postgraduate Award,
while CL, RSL and SEMS acknowledge support from Deakin
University Postgraduate Research Awards. This work is supported by an Australian Research Council Discovery Project
Grant and funding from the Deakin University Central Research
Grant Scheme.
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