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Molecular Immunology 44 (2007) 2497–2506

Review

Cytokine receptor signaling through the Jak–Stat–Socspathway 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 2006Available online 17 January 2007

bstract

The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors

re one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding ofhe cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs),ocussing on their contribution to diseases of an immune or hematologic nature.

2006 Elsevier Ltd. All rights reserved.

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eywords: Cytokine receptor; Jak–Stat–Socs; Inflammatory diseases

. Introduction

The complexity of multicellular organisms is due to the evo-ution of systems enabling cells to respond to distinct cues.ytokines and their specific receptors represent one such sys-

em that plays a key role in blood and immune cells (Satond Miyajima, 1994). Signaling via the largest cytokine recep-or family, the hematopoietin receptors, involves binding of aytokine to a specific receptor chain to initiate formation of aunctional cytokine receptor complex (Kishimoto et al., 1994)Fig. 1). Hematopoietin receptors lack intrinsic tyrosine kinasectivity and instead rely on cytoplasmic kinases, such as Jaks, tonitiate intracellular signaling (Remy et al., 1999). The Jak pro-eins then phosphorylate tyrosine residues within the receptorhains, creating docking sites for dormant cytoplasmic proteins,articularly the Stats. These dimerize and translocate to theucleus, where they function as transcription factors to regu-ate gene expression (Ward et al., 2000). These target genesnclude the Socs genes, whose encoded proteins generally act

n a negative feedback loop to suppress further signaling. Thiseview provides an overview of our current understanding ofematopoietin receptors, Janus kinases (Jaks), Signal transduc-

∗ Corresponding author. Tel.: +61 3 9244 6708; fax: +61 3 9251 7328.E-mail address: award@deakin.edu.au (A.C. Ward).

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rs and activators of transcription (Stats) and Suppressors ofytokine signaling (Socs) and their role in immune and hemato-ogic disease.

. Cytokine receptors

Hematopoietin receptors possess a conserved extracellu-ar region, known as the cytokine receptor homology domainCHD) (Uze et al., 1995), along with a range of other structuralodules, including extracellular immunoglobulin (Ig)-like andbronectin type III (FBNIII)-like domains, a transmembraneomain, and intracellular homology domains (Bazan, 1990;ishimoto et al., 1994). Hematopoietin receptors are divided

nto two classes, which have divergent CHDs (Bazan, 1990).

.1. Class I receptors

Class I cytokine receptors are characterized by two pairs ofonserved cysteines linked via disulfide bonds and a C-terminal

SXWS motif within their CHD (Bazan, 1990). Class I recep-ors fall into three major families, IL-2R, IL-3R and IL-6R, as

etermined by usage of shared receptor chains (Table 1). Eacheceptor complex consists of at least one signal transducingeceptor chain containing membrane-proximal Box 1 and Boxmotifs associated with Jak docking (Leonard and Lin, 2000).

2498 L.A. O’Sullivan et al. / Molecular Imm

Fig. 1. Activation of the Jak–Stat–Socs pathway by cytokine receptors.Cytokines bind to specific cell surface receptors chains, which lead to recep-tor complex formation and the activation of one or more associated Jaks. Thesephosphorylate the intracellular tyrosines of the receptor complex, creating dock-ing sites for Stats, which themselves become tyrosine-phosphorylated forminghomo- or heterodimeric complexes that translocate to the nucleus. Here they bindto specific gene promoters to activate transcription of a range of target genes. Socsgenes are activated by cytokine receptor signaling via the Jak–Stat pathway. Theencoded proteins then act to negatively regulate cytokine signaling in a negativefsf

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eedback loop by three distinct mechanisms: kinase inhibition (of Jaks), binding-ite competition (of Stats) and degradation (of receptor complexes) (modifiedrom Ward et al., 2000).

.1.1. The IL-2R familyThis family predominantly utilizes the common receptor

hain, IL-2R�c, along with a single ligand-specific receptorhain (Ozaki and Leonard, 2002). However, IL-4R� and IL-R� also form additional receptor complexes with other receptorhains (Ozaki and Leonard, 2002), whilst IL-2R� and IL-15R�hains are not hematopoietin receptors, but instead contain dis-inctive ‘sushi domain’ structures (Leonard and Lin, 2000).

embers of the IL-2R family associate with Jak1 and Jak3,rimarily activating Stat5, although certain family members canlso activate Stat1, Stat3, or Stat6 (Gaffen, 2001; Roy et al.,002).

The IL-2R family is primarily involved in the growth andaturation of lymphoid cells (Gaffen, 2001; Parrish-Novak

t al., 2000). For example, the archetypical IL-2R has aange of functions including proliferation of T cells and othermmunoregulatory roles (Gaffen, 2001). Similarly, IL-7R isnvolved in the development of T cells as well as T cell homeosta-is (Fry and Mackall, 2005), IL-4R signaling promotes T helper 2TH2) cell development (Paul, 1997), while IL-21R is involvedn natural killer (NK) cell proliferation and the regulation ofnflammation (Parrish-Novak et al., 2000).

.1.2. The IL-3R familyThis family shares the common signal transducer chain IL-

R�c in combination with specific chains (Boulay et al., 2003;zaki and Leonard, 2002). IL-3R�c is associated with Jak2 and

ignals primarily via Stat5, although activation of other Statsas been observed in certain cell lines (de Groot et al., 1998).

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unology 44 (2007) 2497–2506

he IL-3R family is primarily involved in the production ofyelomonocytic cells. For example, IL-3R signaling is involved

n the differentiation of pluripotent stem cells into variousyeloid progenitor cells (Mangi and Newland, 1999), while IL-is involved in eosinophil development (Roboz and Rafii, 1999).

.1.3. The IL-6R familyThe core IL-6R family members employ the shared recep-

or subunits glycoprotein 130 (GP130), with many also usinghe leukemia inhibitory factor receptor chain (LIFR). GP130ssociates with Jak1, Jak2, and tyrosine kinase 2 (Tyk2), whichctivate Stat1, Stat3 and Stat5 (Heinrich et al., 1998). The IL-12Rubfamily consists of complexes containing the shared recep-ors, IL-12p40 and IL-12R�1, along with the specific IL-12R�2r IL-23R� chain. These activate more specific downstreamomponents: for example, IL-12R specifically activates Stat4,hile IL-23R activates Stat3 (Watford et al., 2004). Unlike otherembers of the IL-6R family, granulocyte colony-stimulating

actor receptor (G-CSFR) and obesity gene receptor (OBR)orm homodimers (Devos et al., 1997; Hiraoka et al., 1994),ut activate similar Jaks and Stats to GP130.

The essential role of the GP130 and LIFR subunits is high-ighted by the lethality of the respective knockout mice (Ware etl., 1995; Yoshida et al., 1996). Individual receptor complexesave more specific roles: ciliary neurotrophic factor receptorCNTFR) promotes survival and differentiation of cells withinhe nervous system (Elson et al., 2000), IL-6R mediates immune,ematopoietic, and thrombopoietic responses (Ito, 2003). TheL-12R family functions in innate immunity (Watford et al.,004), while the G-CSFR plays a key role in granulocytic devel-pment (Lieschke et al., 1994), and OBR is involved in appetiteontrol (Tartaglia et al., 1995).

.1.4. Homomeric receptorsThe erythropoietin receptor (EPOR), thrombopoietin recep-

or (TPOR), prolactin receptor (PRLR), and growth hormoneeceptor (GHR) form homodimers in the presence of theirespective ligands (Heldin, 1995), and associate exclusively withak2 and signal via Stat5 (Boulay et al., 2003). EPOR and TPORre mediators of erythroid (Richmond et al., 2005) and plateletFishley and Alexander, 2004) production, respectively, GHRediates growth and sexual dimorphism (Frank, 2001), whileRLR is involved in mammary development and lactation (Bole-eysot et al., 1998).

.2. Class II receptors

Class II hematopoietin receptors also have two pairs of cys-eines but with a different arrangement to Class I and also lackhe WSXWS motif (Bazan, 1990). The dimerization paradigmf the class II cytokine receptor complex entails a long intracel-ular ligand binding receptor and a short intracellular accessoryeceptor. Only tissue factor (TF), a homodimer, and IL-22BP,

decoy receptor, fail to observe this paradigm. The dimeriza-

ion properties results in 10 receptor complexes formed from aool of 12 class II receptor chains (Kotenko and Langer, 2004)Table 2). Class II cytokine receptors are primarily involved in

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Table 1Structure and function of class I cytokine receptor complexes

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unology 44 (2007) 2497–2506

ntiviral and inflammation modulation, apart from TF that isnvolved in the blood clotting cascade.

.2.1. Antiviral receptorsThere are three receptor complexes that bind to interferons

IFN) to confer antiviral activity, type I IFNR for IFN�/�/�/�/�,ype II IFNR for IFN� and IFN�R for IFN�1–3 (Kotenko andanger, 2004). Both type I IFNR and IFN�R have been shown to

nduce antiviral activity, and signal via Jak2 and Tyk2 in a similartat2-dependent downstream pathways (Kotenko et al., 2003).efects in type I IFN signaling, including a null IFN�R1 muta-

ion, results in immunocompromised mice that are susceptible toiral infections (Hwang et al., 1995). Mice deficient in IFN�R1r IFN�R2 display an increase in susceptibility to pathogenicacteria (Jeanmougin et al., 1998).

.2.2. Non-antiviral receptorsThere is extensive sharing of IL-10R2, IL-20R1, IL-20R2,

nd IL-22R1 with the three cytokine specific receptor subunits,FN�R1, IL-10R and IL-20R1, creating a total of six recep-or complexes. These receptor complexes primarily associateith Jak2 and Tyk2, whilst signaling via Stat1, Stat3 and Stat5

Kotenko and Pestka, 2000). With the exception of IFN�R1,hese receptor subunits modulate the inflammatory responseBlumberg et al., 2001; Conti et al., 2003; Renauld, 2003).

. The downstream Jak–Stat–Socs components

.1. Jaks

Four Jaks have been identified in mammals: Jak1, Jak2,ak3 and Tyk2. Only Jak3 shows restricted expression,eing confined predominately to cells of hematopoietic originKawamura et al., 1994). Jaks posses an N-terminal Four-point-ne/Ezrin/Radixin/Moesin (FERM) domain that appears to bemportant for the interaction between Jaks and their cognateytokine receptor (Chen et al., 1997; Zhao et al., 1995), a centralak homology (JH) 2 pseudokinase domain that serves an essen-ial regulatory role (Saharinen et al., 2000), and a C-terminalH1 kinase domain. In addition to signal transduction, Jak bind-ng may promote cell surface expression of cytokine receptorsHuang et al., 2001).

.2. Stats

Seven Stat family members have been identified in mam-als: Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b and Stat6. Each

s composed of five essential domains, including a four helixundle transactivation domain, a central �-barrel Ig-like DNAinding domain, a helical linker domain, an SH2 domain and anffector domain (Neculai et al., 2005). Stat specificity is largelyetermined by the binding preference of their SH2 domains forhosphorylated tyrosines on specific receptors, although cell

ype and differentiation state also contributes. In addition, forma-ion of heterodimers, tetramers and other higher order complexesxpands the range of Stat/DNA binding opportunities (Ward etl., 2000).

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.3. Socs

Eight mammalian Socs proteins have been identified:ocs1–7 and cytokine-inducible SH2 protein (Cis). Membersf the Socs family of proteins possess three domains: an-terminal domain of variable length that is not well con-

erved between members and whose function remains largelynknown; a central SH2 domain, required for interaction witharget phosphotyrosine residues; and a highly conserved C-erminal domain known as the Socs box, believed to be involvedn proteasomal targeting (Zhang et al., 1999). Socs proteins canegatively regulate cytokine receptor signaling by several dis-inct mechanisms. Firstly, they can directly inhibit Jak kinasesy binding to the receptor or to the Jak activation loop (Endot al., 1997). Secondly, they can compete with other signal-ng molecules containing SH2-domains for binding sites onhe receptor (Matsumoto et al., 1997). Thirdly, they can tar-et the receptor complex and associated signaling proteins forroteasomal degradation through the Socs box, which mediatesnteractions with elongins B and C to recruit an E3 ubiquitinigase complex (Hilton et al., 1998; Zhang et al., 1999).

. The cytokine receptor-Jak–Stat–Socs pathway inisease

Perturbation of cytokine receptor signaling has importantathological consequences, particularly with respect to immunend blood cells. These can affect the development or func-ion of specific cell populations in either a positive or negative

anner. Therefore, immune and hematopoietic deficiencies arebserved, as well as excess production and/or activation of spe-ific cell populations, including malignancy.

.1. Severe combined immunodeficiency

The majority of cases of severe combined immune deficiencySCID) can be attributed to defects in signaling by members ofhe IL-2R family (Buckley, 2004). The most common form ofhe disease, termed X-linked SCID, is due to a mutation of theL-2R�c gene (Kovanen and Leonard, 2004). Since IL-2R�c ishe common signal transducer of the IL-2R family, this leadso simultaneous perturbation of signaling for several cytokines,nd so patients suffer severe immune defects, manifested in theotal loss of T and NK cells (Buckley, 2004; Ozaki and Leonard,002). A phenotypically similar, but autosomal recessive form ofCID, with a lack of T and NK cells and impaired mature B cellunction, is caused by mutations in Jak3, the main signal trans-ucer for IL-2R�c (Pesu et al., 2005). Finally, mutations of theL-7R� are associated with a milder form of SCID, characterizedy a specific lack of T cells (Buckley, 2004; Puel et al., 1998).

.2. Other immunodeficiencies

Defects in class II receptor signaling components produceore subtle and specific immune deficiencies. Nonsense muta-

ions prior to the transmembrane domain of IFN�RI results inn absence of cell-surface expression leading to compromised

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unology 44 (2007) 2497–2506 2501

mmunity, particularly increased susceptibility to mycobacterialnfection and mortality (Jouanguy et al., 2000). Patients withoss-of-function Stat1 (L706S) mutation are also susceptible to

ycobacterial infection (Dupuis et al., 2001), consistent withhe involvement of this Stat in both types I and II IFNR signal-ng. Finally, a spontaneously occurring murine Tyk2 mutant isighly sensitive to Toxoplasma gondii infection, due to impairedL-12R responses (Shaw et al., 2003).

.3. Inflammatory diseases

Several different inflammatory diseases have been shown toe due to abnormalities in cytokine receptor signaling pathways,rincipally in T cells. For example, in Crohn’s disease, an inflam-atory disease of the colon and small intestine, constitutive

ctivation of both Stat3 and Stat5 have been observed specif-cally in the intestinal T cells (Lovato et al., 2003). Patients withhronic obstructive pulmonary disease patients also show highevels of activated Stat4, which correlate with an increase in lungnjury. In this case, it is thought to be due to excess IL-12R signal-ng, and that the hyperactivated Stat4 induces T cells toward theH1 type, potentially damaging the lung tissue (Di Stefano et al.,004). Asthmatic patients also show activation of Stat1, whichlso correlated with an increase in T cell accumulation (Sampatht al., 1999). In addition, certain polymorphisms of Stat6 haveeen linked to allergic diseases (Tamura et al., 2003). In supportf this, Stat6 knockout mice are resistant to certain inflammatoryonditions (Kuperman et al., 2002). Patients with TH2 type dis-ases, such as atopic asthma and dermatitis also show a high levelf SOCS3 expression in peripheral T cells, which is tightly cor-elated with severity of disease (Seki et al., 2003). In contrast,ocs1 has been implicated as an important negative regulatorf various inflammatory diseases including rheumatoid arthritisRA) and systemic lupus erythematosus (SLE) although this isrobably via its effects on IFN receptor signaling (Egan et al.,003; Ernst et al., 2001; Fujimoto et al., 2004).

.4. Autoimmune disorders

A range of autoimmune disorders also involve dysregulatedignaling of several cytokine receptor types. For example, twoolymorphisms in the FERM domain of Tyk2 are associatedith decreased susceptibility to systemic autoimmune disease

SLE) that is characterized by arthritis, skin rashes, nephritis,nd vasculitis among other symptoms (Sigurdsson et al., 2005).his is believed to be due to a loss in Type I IFNR signaling,hich is supported in IfnαR deficient mice that show reducedLE disease and mortality (Santiago-Raber et al., 2003). In con-

rast, humans with allergic conjunctivitis showed a correlationetween the level of expression of Socs3 with the clinical, patho-ogical and severity of the diseases (Ozaki et al., 2005; Seki etl., 2003). A similar role for Socs5 has also been reported in aouse model of this disease (Ozaki et al., 2005), as well murine

xperimental autoimmune uveitis, an autoimmune disease of theetina (Takase et al., 2005). Peripheral blood mononuclear cellsrom patients suffering from uveitis also have significantly ele-ated SOCS5 mRNA, but when given anti-IL-2R� therapy, the

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xpression levels significantly reduced, suggesting this is due toyperactivated T cell signaling through the IL-2R (Egwuagu etl., 2005).

.5. Infectious disease pathogenesis

Cytokine signaling components are also specifically targetedy infectious agents to facilitate infection. For example, measlesirus infection is augmented by suppression of type I IFNR-nduced antiviral responses (Yokota et al., 2003). In contrast,he Hepatitis C virus (HCV) protein NS5A interacts with andctivates Jak1, which in turn activates Stat3 and so contributeso the progression of HCV related disease (Sarcar et al., 2004).inally, patients infected with HIV show reduced expression oftat5 in T cells (Pericle et al., 1998), but constitutive activationf Stat proteins in other cells (Bovolenta et al., 1999).

.6. Hematological defects

A range of haematological defects have been associated withutations in specific class I cytokine receptors. Thus, mis-

ense and truncating mutations of TPOR have been describedn patients with congenital megakaryocytic thrombocytopenia,haracterized by reduced platelet numbers in the blood (Fishleynd Alexander, 2004). Two classes of G-CSFR mutations haveeen described in severe congenital neutropenia patients (Ward,007): extracellular mutants that lead to a hyporesponsiveness to-CSF therapy (Ward et al., 1999), as well as intracellular trun-

ation mutants (Dong et al., 1995). Finally, mutations of IL-3R�cave been found in several pediatric pulmonary alveolar pro-einosis patients, who show alveolar accumulation of phospho-ipids and proteins derived from surfactant proteins due in part toefective alveolar macrophage function (Dirksen et al., 1997).

.7. Myeloproliferative disorders

Other (hyperactivating) mutations affecting class I cytokineeceptor signaling pathway are found associated with severalyeloproliferative diseases. A missense mutation within the

ransmembrane domain of TPOR leads to familial essentialhrombocythemia, a disorder characterized by elevated plateletevels and megakaryocyte levels in the blood and bone marrow,espectively (Fishley and Alexander, 2004), a polymorphism inhe intracellular domain of G-CSFR shows a strong associationith myelodysplastic syndromes (Wolfler et al., 2005), while

runcation of EPOR has been implicated in erythrocytosis, aenign proliferative condition affecting red blood cells (de lahapelle et al., 1993). In addition, heterozygous and homozy-ous V617F mutations within the JH2 domain of Jak2 haveeen identified in a high percentage of classical myeloprolif-rative disorders, including patients with polycythemia vera,ssential thrombocythemia and idiopathic myelofibrosis (Baxtert al., 2005; James et al., 2005; Kralovics et al., 2005; Levine et

l., 2005), and at a lower frequency in other myeloproliferativeisorders (Steensma et al., 2005). These mutations result in con-titutive tyrosine phosphorylation of Jak2, promoting cytokineeceptor hypersensitivity (James et al., 2005).

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unology 44 (2007) 2497–2506

.8. Leukemias/lymphomas

Inappropriate activation of class I cytokine receptor signal-ng also appears to be a hallmark of a range of malignancies,ncluding leukemias and lymphomas. For example, the IL-3R�hain is overexpressed in blast cells from >80% of acute myeloideukemia (AML) patients, leading to increased downstreamignaling, particularly of Stat5 (Testa et al., 2004). In otherML patients, a truncated form of IL-3R�c, IL-3R�IT, is over-

xpressed and leads to a disruption of normal signaling (Galet al., 1998). Similarly, a C-terminally truncated version of G-SFR, also leading to hyperactivation of Stat5 (Gits et al., 2007),

s observed in a group of severe congenital neutropenia patientsredisposed to AML, while alternate G-CSFR mutations areeen in cases of de novo AML (Touw and Dong, 1996).

A range of genetic changes leading to hyperactivation ofak2 are associated with leukemia. Three alternate translocationsave been identified between the transcription factor TEL/ETV6nd Jak2 in early pre-B acute lymphoid leukemia (ALL), atyp-cal chronic myelomonocytic leukemia CML and T cell ALLLacronique et al., 1997; Peeters et al., 1997). More recently,chimeric protein produced by a translocation of PCM1 with

ak2 has also been identified in atypical CML (Bousquet et al.,005). In addition, Jak2 V617F mutations have been observedn AML, CML and chronic neutrophilic leukemia (Steensma etl., 2005), as well as a K607N mutation in AML (Lee et al.,006). Finally, amplification of genomic regions encompassinghe Jak2 gene has been seen in Hodgkin’s lymphoma patientsJoos et al., 2000).

Constitutive activation of Stats is also a common observationn malignancy. This includes Stat1 in AML, B cell ALL, ery-hroleukemia and Epstein-Barr virus related lymphomas (Wardt al., 2000; Weber-Nordt et al., 1996), Stat3 in Hodgkinsisease, AML and human T cell lymphoma virus (HTLV)ependent T cell leukemia (Calo et al., 2003; Catlett-Falconet al., 1999; Dolled-Filhart et al., 2003; Hayakawa et al., 1998;ovato et al., 2003), and Stat5 in erythroleukemia, AML, CML,LL, megakaryocyte leukemia and HTLV dependent T cell

eukemia (Ward et al., 2000). It is also often triggered byeukemic oncoproteins, which include Tel-Jak2 (Lin et al., 2000)nd Bcr-Abl (Shuai et al., 1996). Stat3 and Stat6 have been con-titutively activated in Hodgkins Disease. In particular 78% ofhe Reed-Sternberg cells of classical Hodgkin’s lymphoma showonstitutive Stat6 phosphorylation (Skinnider et al., 2002).

In contrast, Socs1 appears to act as a tumor suppressor. Thus,ethylation and subsequent inactivation of the SOCS1 gene has

een observed in a variety of human cancers, including around0% of newly diagnosed AML (Chen et al., 2003). CML patientslso demonstrate SOCS1 methylation that reverts to an unmethy-ated state during remission (Liu et al., 2003).

. Conclusions

The dissection of cytokine receptor signaling and the role ofts various components in health and disease point to some gen-ral conclusions. Firstly, many of the components have specificelationships that mediate relatively narrow functions, espe-

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ially in immune or hematologic function. Thus, the IL-2Ramily exclusively engages Jak3, Stat4 and Stat6 to assist inhe development of acquired immunity, while the IFNs almostxclusively engage Tyk2, Stat1, Stat2 and Socs1 to mediate andodulate antiviral and inflammatory responses. Another keyodule appears to be the Jak2–Stat5–Cis pathway, although this

s employed via a diverse range of receptors, for example, by theL-3R family to produce and regulate cells of the innate immuneystem, by EPOR to perform a similar role for red blood cells,ut also by PRLR and GHR, although the later recruits Socs2s well. True pleiotropy is the exception, largely limited to IL-receptor family, Jak2, Stat3, Socs1 and Socs3. In addition,

ome components are involved in alternate paradigms, includ-ng TF, Socs6 and Socs7. Secondly, and somewhat related tohe first point, many mutations or perturbations of componentsonverge at the disease level. For example, mutations in severalf the IFN components lead to reduced response to infectiousisease. Enhanced signaling (mediated by hyperactive/receptorutations, activating Jak mutations, constitutive active Stats, or

uppression of Socs expression) can cause proliferative disor-ers, particularly of a hematological, or inflammatory nature.owever, this means there is considerable potential to develop

ommon disease therapeutics for such diseases and that multipleargets can also be considered simultaneously.

cknowledgements

LAO’S is a recipient of an Australian Postgraduate Award,hile CL, RSL and SEMS acknowledge support from Deakinniversity Postgraduate Research Awards. This work is sup-orted by an Australian Research Council Discovery Projectrant and funding from the Deakin University Central Researchrant Scheme.

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