Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

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∗

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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).

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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-

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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. References Baxter, E.J., Scott, L.M., Campbell, P.J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G.S., Bench, A.J., Boyd, E.M., Curtin, N., Scott, M.A., Erber, W.N., Green, A.R., 2005. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054–1061. Bazan, J.F., 1990. Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl. Acad. Sci. U.S.A. 87, 6934–6938. Blumberg, H., Conklin, D., Xu, W., Grossmann, A., Brender, T., Carollo, S., Eagan, M., Foster, D., Haldeman, B.A., Hammond, A., 2001. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19. Bole-Feysot, C., Goffin, V., Edery, M., Binart, N., Kelly, P.A., 1998. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr. Rev. 19, 225–268. Boulay, J.L., O’Shea, J.J., Paul, W.E., 2003. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 19, 159–163. Bousquet, M., Quelen, C., De Mas, V., Duchayne, E., Roquefeuil, B., Delsol, G., Laurent, G., Dastugue, N., Brousset, P., 2005. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene. Oncogene 24, 7248–7252. Bovolenta, C., Camorali, L., Lorini, A.L., Ghezzi, S., Vicenzi, E., Lazzarin, A., Poli, G., 1999. Constitutive activation of Stats upon in vivo human immunodeficiency virus infection. Blood 12, 4202–4209. Buckley, R.H., 2004. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu. Rev. Immunol. 22, 625–655.

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