Hematopoietic Cytokine Receptor Signaling

Home , GRB2, Janus kinase 1, PIAS1, PIAS3, SOCS4, SOCS5

SJ Baker1, SG Rane2 and EP Reddy1

1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA and 2National Institutes of Health, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA

Hematopoiesis is the cumulative result of intricately stem cell-like properties, their fate is more restricted regulated signaling pathways that are mediated by toward a particular lineage as it has been possible to cytokines and their receptors. Proper culmination of these isolate common lymphoid and common myeloid diverse pathways forms the basis for an orderly generation progenitor cells that display preferences to the lymphoid of different cell types. Recent studies conducted over the and myeloid lineages, respectively. Common lymphoids past 10–15 years have revealed that hematopoietic cytokine will ultimately develop into T and B lymphocytes, receptor signaling is largely mediated by a family of whereas common myeloid progenitors will eventually tyrosine kinases termed Janus kinases (JAKs) and their give rise to erythrocytes, megakaryocytes (Meg-E fate) or downstream transcription factors termed STATs (signal monocytes/macrophages and granulocytes (GM fate) transducers and activators of transcription). Aberration in (reviewed in Rosmarin et al., 2005). Over the past few these pathways, such as that caused by the recently decades, dedicated work from many groups has estab- identiﬁed JAK2V617F mutation, is an underlying cause lished that hematopoietic cell growth and differentiation for diseases such as leukemias and other myeloproliferative are mediated by a group of soluble factors known as disorders. This recent discovery, when coupled with the fact cytokines (Hunter, 1993; Stahl and Yancopoulos, 1993; that STATs are activated by oncoproteins such as BCR- Kishimoto et al., 1994; Taniguchi, 1995). ABL, underscores the importance of the JAK-STAT pathway in both normal cellular development and disease states. Oncogene (2007) 26, 6724–6737; doi:10.1038/sj.onc.1210757 Cytokines and their receptors

Keywords: hematopoiesis; cytokine receptors, Src ki- Cytokines are a group of polypeptide growth factors that nases; JAKs; STATs bind to their cognate receptors and mediate intracellular signaling events that result in the modulation of gene expression. At the basic structural level, most cytokine receptors consist of a multisubunit complex: a unique and specific ligand-binding subunit and a signal-transdu- Introduction cing subunit, which may be structurally similar to other members of the cytokine receptor superfamily (Hunter, From embryogenesis to adulthood, hematopoiesis occurs 1993; Stahl and Yancopoulos, 1993; Kishimoto et al., via a series of proliferative and differentiative pathways, 1994; Taniguchi, 1995). The average extracellular do- where pluripotent, multipotent and lineage-committed main comprises approximately 210 amino acids and cells and intermediates develop into various types of contains one or more conserved cysteine (C) residues. mature and functional blood cells. At each stage of this In addition, a second conserved sequence of trypto- process, a precursor cell must divide and expand before phan–serine–X–tryptophan–serine (W-S-X-W-S), where further differentiating along a given pathway to maintain X refers to any non-conserved amino-acid residue, is steady-state levels of each cell type. Hematopoietic stem present in the C terminus (Miyajima et al., 1992). cells lay the groundwork for this hierarchy and are Structurally, this region is also composed of two maintained in constant numbers in the bone marrow, fibronectin type III modules. A hinge region connects where they are found in a quiescent state (reviewed in these two modules, each of which comprises approxi- Ema and Nakauchi, 2003; Durand and Dzierzak, 2005). mately 100 amino acids. This region, which also houses According to simplified models, after a series of the W-S-X-W-S motif, is predicted to function as a divisions, pluripotent hematopoietic stem cells will yield ligand-interaction domain. Site-directed mutational ana- committed progenitor cells. Although these cells retain lysis within the hinge region, particularly the W-S-X-W- S motif, abolishes or greatly reduces the ligand-binding capacity of the receptors (Barry et al., 1997). The cyto- Correspondence: Dr EP Reddy, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 plasmic domains of cytokine receptors share a limited North Broad Street, Philadelphia, Pennsylvania, PA 19140, USA. level of similarity in their membrane proximal regions, E-mail: [email protected] particularly in regions termed the box 1 or the proline-rich JAKs and STATs in cytokine signaling SJ Baker et al 6725 motif and the box 2 motif (box 1/proline-rich above-mentioned receptors possesses a unique and motifs are characterized by the sequence Al–Ar–Pro–X– specific ligand-binding a-subunit. Al–Pro–X–Pro or Ar–X–X–X–Al–Pro–X–Pro, where Al ¼ aliphatic; Ar ¼ aromatic; and X ¼ any amino acid). These portions of the receptor are critical for proper The interleukin-2 receptor family: cytokines that function of the receptor and mediating mitogenic signal through a common c-chain and a- and/or signals. In contrast, the membrane distal region, which b-ligand-binding subunits also contains box 1 and two motifs, is required for differentiation. Functions of regions within the The IL-2 receptor (IL-2R) consists of three subunits, a, cytoplasmic domains that do not contain box 1 or box b and g, of which the g-chain (IL-2Rg-chain) is shared 2 motifs vary from receptor to receptor (reviewed in Ihle by receptors for IL-4, IL-7, IL-9 and IL-15. Each of et al., 1995). these receptors, similar to the IL-2R, consists of three Although hematopoietic cytokine receptors are subunits, termed a, b and g. Of these, the a-subunit grouped together as such due to the presence of shared acts as the ligand-binding subunit, whereas the b-and motifs within their extracellular domains, they can be g-subunits function as signal-transducing subunits. The further subdivided into families based on the number of IL-2Rg-chain associates with Janus kinase-3 (JAK3) subunits and/or the presence of one or more shared and mutations in either IL-2Rg-chain or JAK3 result in subunits (Hunter, 1993; Stahl and Yancopoulos, 1993; a non-functional receptor, which abrogates signaling via Kishimoto et al., 1994; Ihle et al., 1995; Taniguchi, IL-2, IL-7, IL-9 and IL-15 (Russell et al., 1994, 1995). 1995). The main cytokine receptor subtypes are (i) those that signal through gp130 or a gp130-related subunit, (ii) those that signal through a common g-chain (gc) and a- and/or b-ligand-binding subunits, (iii) those that The growth hormone family: cytokines that signal through signal through a single chain, (iv) those that signal a single chain through two or more subunits and (v) those that signal through the gp140b-subunit and a ligand-binding a- This family includes receptors for growth hormone, subunit (Figure 1). A detailed description of the features prolactin (PRL), erythropoietin (EPO), granulocyte- of each of these families is beyond the scope of this colony-stimulating factor and thrombopoietin. These review, and hence we only provide a few salient features receptors consist of a single subunit that forms homo- of these protein families. dimers upon ligand binding. Although structurally similar, they do not crossreact with ligands of other receptors and transduce signals that are specific for a given cytokine. The gp130family: cytokines that signal through gp130or a gp130-related subunit The interferon family: cytokines that signal through two Receptors for interleukin-6 (IL-6), IL-11, IL-12, cardio- or more subunits tropin-1, ciliary neurotrophic factor, oncostatin M and leukemia inhibitory factor, all signal through a This family comprises the interferon (IFN)-a receptor common b-chain termed gp130. Apart from this (IFNAR), the IFN-g receptor (IFNGR) and the common gp130 signal-transducing subunit, each of the IL-10R. The IFNGR also has two chains, IFNGR1

shared gp140, gp-130/ γ ligand-specific shared c subunit, gp-130 related α subunit ligand-specific α 2 or more β signaling and/or subunits distinct domain subunits Single chain γ β α c c α α (gp140) β gp130 c IFNRI IFNRII IL-3 IL-2 IL-6 IL-5 IFNα /β IL-4 LIF GM-CSF IFN γ EPO IL-7 OSM G-CSF IL-9 IL-11 PRL IL-15 GH IL-12 CTNF CT-1 Figure 1 Schematic representation of cytokine receptor families. The structure of ﬁve superfamilies and their respective members are depicted (note: not drawn to scale).

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6726 and IFNGR2. The IL-10R comprises two chains, IL- Table 1 Jaks and STATs activated by cytokine receptors 10R1 and IL-10R2. In the case of these receptors, both Cytokine Jak STAT subunits function as signal-transducing components of the receptor and bind to downstream signaling proteins CNTF Jak1, Jak2, Tyk2 Stat3 such as JAKs and signal transducers and activators of CT-1 Jak1, Jak2, Tyk2 Stat3 Epo Jak2 Stat5a, Stat5b transcriptions (STATs). GH Jak2 Stat3, Stat5a, Stat5b G-CSF Jak2, Jak3 Stat3 GM-CSF Jak2 Stat5a, Stat5b IFN-a/b Jak1, Tyk2 Stat1, Stat2 The gp140family: cytokines that signal through the IFN-g Jak1, Jak2 Stat1 gp140b-subunit and a ligand-binding a-subunit IL-2 Jak1, Jak2, Jak3 Stat3, Stat5a, Stat5b IL-3 Jak2 Stat3, Stat5a, Stat5b This family includes the receptors for cytokines, IL-3, IL-5 IL-4 Jak1, Jak3 Stat6 IL-5 Jak2 Stat1, Stat3, Stat5a, Stat5b and granulocyte macrophage-colony-stimulating factor. IL-6 Jak1, Jak2, Tyk2 Stat1, Stat3 The IL-3 and GM-CSF genes located on the 5q region of IL-7 Jak1, Jak3 Stat3, Stat5a, Stat5b chromosome 5 have been associated with hematopoietic IL-9 Jak3 Stat3, Stat5a, Stat5b malignancies, underlining the importance of these cyto- IL-10 Jak1, Tyk2 Stat1, Stat3 kines in hematopoietic signaling (Blalock et al., 1999). The IL-11 Jak1, Jak2, Tyk2 Stat3 IL-12 Jak2, Tyk2 Stat4 receptors for these cytokines have unique ligand-binding-a IL-13 Jak1, Jak2, Tyk2 Stat6 chains and share the common b (gp140) signal-transdu- IL-15 Jak1, Jak3 Stat3, Stat5a, Stat5b cing subunit (Gearing et al., 1989; Hayashida et al., 1990; LIF Jak1, Jak2, Tyk2 Stat3 Itoh et al., 1990; Murata et al., 1992). OSM Jak1, Jak2, Tyk2 Stat3 PRL Jak2 Stat5a, Stat5b Tpo Jak2, Tyk2 Stat5a, Stat5b

Signal-transduction pathways activated by cytokines Abbreviations: CNTF, ciliary neurotrophic factor; GH, growth harmone; G-CSF, granulocyte-colony-stimulating factor; GM-CSF, granulocyte macrophage-colony-stimulating factor; IFN, interferon; Molecular cloning of cytokine receptors and subsequent IL, interleukin; JAK, Janus kinases; LIF, leukemia inhibitory factor; structure–function studies has revealed that unlike growth OSM, oncostatin M; PRL, prolactin; STAT, signal transducers and factor receptors, cytokine receptors are devoid of catalytic activators of transcription. activity. Nevertheless, interaction of a cytokine with its receptor rapidly induces tyrosine phosphorylation of the residues that are required for catalytic activity and receptor and a variety of cellular proteins, suggesting that nucleotide binding. However, it is now clear that this these receptors transmit their signals through cellular kinase-like domain plays a significant regulatory role in tyrosine kinases (Kishimoto et al., 1994). During the past the activity of both JAK family proteins and cytokine- 10–15 years, a large amount of experimental data have induced signaling. For example, deletion of the JH2 accumulated to indicate that most cytokines transmit their domain in both Jak2 and Jak3 has been shown to result signals via a distinct family of tyrosine kinases termed in increased phosphorylation of these mutants as well as Janus kinases or JAKs (Table 1; Ihle et al., 1997; Darnell STAT-5 (Saharinen et al., 2000; Saharinen and Silven- et al., 1994). noinen, 2002), suggesting that this domain is required for inhibiting the basal activity of these proteins. Furthermore, expression of these JH2-deficient proteins Janus kinases in factor-dependent cell lines results in cytokine- independent signaling. A more detailed analysis of the There are four members of the JAK family, JAK1, Jak2 JH2 region using recombinant proteins indicates JAK2, JAK3 and TYK2. Of these, TYK2 was the first to that this domain suppresses basal JAK2 activity by be discovered (Firmbach-Kraft et al., 1990) and bore lowering the Vmax of the kinase without affecting its Km some resemblance to known tyrosine kinases. Shortly for a substrate peptide (Saharinen et al., 2003). thereafter, cDNAs encoding JAK1 (Wilks et al., 1991), Additional studies have revealed the presence of three JAK2 (Harpur et al., 1992) and JAK3 (Kawamura et al., inhibitory regions (1–3) that regulate the autoinhibitory 1994; Rane and Reddy, 1994; Takahashi and Shirasawa, activity of this kinase as well as a novel phosphorylation 1994) were isolated using various cloning strategies. site at tyrosine 570 that regulates responses to cytokines The unique structure of the JAKs clearly distinguishes (Saharinen et al., 2003; Feener et al., 2004). Taken them from other members of the protein tyrosine kinase together, these studies indicate that the JH2 domain is family (Figure 2). The most intriguing feature of these critical in the ability of JAKs to regulate themselves as proteins is the presence of two Jak homology (JH) well as mediate cytokine-induced responses. domains, JH1 and JH2, which have extensive homology The importance of the JH2 domain in the regulation to tyrosine kinase domains. Although the JH1 domain is of JAK activity has been recently underscored in a functional tyrosine kinase domain, the JH2 domain, patients suffering from myeloproliferative disorders, in despite harboring most of the conserved amino acids particular, those whose cells express the mutant that are a characteristic of functional kinases, lacks any JAK2V617F protein (Baxter et al., 2005; James et al., observable tyrosine kinase activity due to the absence of 2005; Kralovics et al., 2005; Levine et al., 2005). This

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6727 FERM SH2 PSEUDO TK TK

V617F JH7 JH6 JH5 JH4JH3 (Jak2) JH2 JH1

Figure 2 Structure of Janus kinases (JAKs). JAKs harbor four functional domains, the FERM domain, the SH2 domain, the pseudotyrosine kinase (TK) domain and a catalytically active TK domain. Although the JH2 region is not a functional tyrosine kinase, this domain negatively regulates the activity of JAK proteins. Also shown are the FERM and SH2 domains, which serve as receptor association and phosphotyrosine-binding domains, respectively, and the Jak2V617F mutation that is found in myeloproliferative disorders. mutation is believed to disrupt the inhibitory role that role in signal transduction in general. However, the the JH2 domain has on JH1, whereby the activation complexity associated with processing signals from such loop of JH1 adopts a conformation such that it can be diverse sources suggests a complicated mechanism of phosphorylated by an adjacent JAK2V617F molecule. As action for JAKs. Although the precise mechanism by a result, cells that express this protein display increased which ligand binding results in the activation of JAKs is levels of phosphorylated, activated JAK2. In addition, a not known, inferences from the results of various studies number of severe combined immunodeficiency patients have allowed the proposition of models to explain the have mutations in the JH2 domain of JAK3 (reviewed in mechanism of activation of JAKs. JAKs, when ectopi- O’Shea et al., 2002), further signifying the role that this cally expressed in the baculovirus system, are enzyma- domain plays in the regulation of JAK proteins. tically active and are phosphorylated on tyrosine At the time the JAKs were cloned and initially residues. Their overexpression in mammalian cells also characterized, it was believed that the sequences of the leads to constitutive activation, most probably due to JH3–JH7 domains bore little resemblance to any dimerization (Colamonici et al., 1994a, b; Yamamoto characterized protein motif. However, it is now widely et al., 1994; Duhe and Farrar, 1995; Quelle et al., 1995; accepted that the N-terminal-half of JAKs contains two Wang et al., 1995; Eilers et al., 1996). On the other hand, motifs, an Src homology-2 (SH2) domain and a band a JAK in complex with a native un-liganded receptor is Four-point-one, Ezrin, Radixin, Moesin (FERM) do- in a catalytically inactive latent state. Receptor dimer- main. The SH2 domain encompasses what is defined as ization/oligomerization due to ligand binding results in the JH3 and JH4 domains. However, in spite of the the juxtapositioning of the JAKs, which are in the homology to SH2 sequences, this region does not appear vicinity through either homo- or heterodimeric interac- to bind to phosphotyrosine residues (Higgins et al., 1996; tions. The recruitment of JAKs appears to result in their Kampa and Burnside, 2000; reviewed in Haan et al., phosphorylation, either via autophosphorylation and/or 2006). The JH6–JH7 domains comprise the FERM cross phosphorylation by other JAKs or via other domain, which regulates catalytic activity and mediates families of tyrosine kinases. This activation is presumed association with receptors and other proteins. Residues to result in increased JAK activity. Activated JAKs then located in the JH7 domain mediate binding to the box 1/ phosphorylate receptors on target tyrosine sites. The proline-rich region of cytokine receptors (Pellegrini and phosphotyrosine sites on the receptors can then serve as Dusanter-Fourt, 1997; Richter et al., 1998; Haan et al., docking sites that allow the binding of other SH2- 2002). In addition, this interaction between JAKs and domain containing signaling molecules such as STATs, cytokine receptors ultimately regulates receptor localiza- Src-kinases, protein phosphatases and other adaptor tion and turnover (Gauzzi et al., 1997; Ragimbeau et al., signaling proteins such as Shc, Grb2 and phosphatidy- 2003). Specifically, surface expression of EPO receptor linositol 3-kinase (PI3K) (Figure 3; reviewed in Woj- can be regulated by the FERM domain of JAK2 (Huang chowski et al., 1999). et al., 2001), and both JAK2 and TYK2 have been The above model is supported by several studies shown to inhibit the proteasomal degradation of the where investigators have demonstrated the ability of thrombopoietin receptor by facilitating its expression at cytokines such as EPO to rapidly induce receptor the cell surface. Recently, Funakoshi-Tago et al. (2006) oligomerization leading to JAK2 activation (Watowich have identified a regulatory tyrosine residue in JAK2, et al., 1994). Furthermore, studies using chimeric Y119, which when phosphorylated following receptor receptors with various combinations of extracellular dimerization, causes the protein to dissociate from the ligand binding and cytoplasmic domains also favor this receptor and undergo degradation. Thus, JAK FERM model (Jubinsky et al., 1993; Eder et al., 1994; domains can both positively and negatively regulate the Watowich et al., 1994; Ihle et al., 1995), which readily protein’s ability to mediate responses to cytokines. applies to both single-chain receptors such as those for EPO, PRL, growth hormone and granulocyte-colony- stimulating factor as well as multichain receptors such as Receptors are primary substrates of Janus kinases those for IL-3, IL-5 and GM-CSF. Cytokine binding activation results in the association of the JAKs with one of the subunits. The receptor-associated JAK either can then The importance of JAKs in mediating signals from a process the signal or, subsequent to receptor oligomeri- variety of cytokines/growth factors underscores their zation, can recruit other JAKs in the vicinity. Homo- or

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6728

Src JAK p p RAF JAK p PI3K STAT p AKT ERK

p STAT STAT p

nucleus p p STAT STAT

Figure 3 Signaling pathways mediated by JAKs. Ligand binding to cytokine receptors induces their dimerization. JAKs, which bind to the receptor via their SH2 domains, undergo transphosphorylation and subsequently phosphorylate STATs. The activated STATs dimerize, translocate to the nucleus whereby they activate or repress target gene promoters. STATs can also be directly activated by Src kinases. In this model, JAKs phosphorylate the receptor and create binding sites for STATs. In addition to JAKs and STATs, cytokine receptors also activate additional signaling pathways involving proteins such as Akt and extracellular responsive kinase. JNKs, Janus kinases; STAT, signal transducers and activators of transcription.

heterodimerization of the JAKs followed by their transducers and activators of transcription, or STATs. activation upon phosphorylation finally results in the These transcription factors were originally described by propagation of the initial signal. Darnell et al. (1994, 1997) as ligand-induced transcrip- The JAK2V617F mutation clinically signifies the im- tion factors in IFN-treated cells. Subsequent studies by portance of the interaction between cytokine receptors a number of groups showed that STATs play a critical and JAKs. This gain-of-function mutant, unlike the role in signal-transduction pathways triggered by several chimeric JAK2 fusion proteins that result from chromo- cytokines and neurokines (Table 1; reviewed in O’shea somal translocations, does not contain dimerization et al., 2002). To date, seven mammalian STAT-encoding sequences and thus, is monomeric and unable to genes have been identified. Alternative splicing or post- phosphorylate another molecule, in trans, in the absence translational proteolytic cleavage reactions appear to of cytokine (reviewed in Valentino and Pierre, 2006). generate additional forms of STAT-1 and -3. Thus, two However, in cells that express sufficient levels of a isoforms of STAT-1 have been described, which have homodimeric type I cytokine receptor, such as Epo been termed as STAT-1a or p91 and STAT-1b or p84. receptor or granulocyte-colony-stimulating factor recep- STAT-3 also exists in two forms, termed STAT-3a and tor, JAK2V617F can promote proliferation in the absence -3b, with different transcriptional activation functions of cytokine. In this situation, the receptor is predicted to (Schaefer et al., 1995). STAT-4 also exists in two forms, act as a scaffold, whereby each chain of the homodimer termed STAT-4a and -4b. Two STAT-5 isoforms, binds to JAK2V617F, thereby allowing the kinase to termed STAT-5a and -5b, are encoded by two separate undergo trans-phosphorylation (Lu et al., 2005). genes that are linked in tandem (Copeland et al., 1995; Lin et al., 1996). The two proteins exhibit extensive sequence homology and differ from each other mainly in the N- and C-terminal domains, with the transactivation Signal transducers and activators of transcription domain being the most divergent. Similar to most transcription factors, STATs exhibit a A little more than a decade ago, researchers deciphered modular structure with six well-defined domains, a signaling pathway that initiates within the cytoplasm including an N-terminal-conserved domain, a coiled- but quickly translocates to the nucleus to activate coil domain, a DNA binding domain, a linker region, an transcription of target genes. This signaling pathway SH2 domain and a C-terminal transactivation domain features a group of transcription factors termed signal (Figure 4). The N-terminal region of STATs is well

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6729 conserved among family members and appears to be homo- and heterodimerization, which in turn appears to critical for STAT function, as small deletions in this be critical for nuclear localization and DNA-binding region have been shown to eliminate the ability of activities. The transactivation domain varies among STATs to be phosphorylated. This domain also func- family members and, as the name implies, modulates tions in nuclear import, export, receptor binding and the transcriptional activation of target genes. The cooperates with the DNA-binding domain. The coiled- C-terminally truncated isoforms of STAT-3, -4 and -5 coil domain adopts an a-helical conformation, functions are missing portions of their transactivation domains in receptor binding and associates with regulatory and reportedly behave as dominant-negatives (reviewed proteins (reviewed in Kisseleva et al., 2002). The in Schindler and Strehlow, 2000). DNA-binding domain is also highly conserved among In an unstimulated cell, STATs are monomeric, the STATs, and all STAT homodimers with the cytosolic proteins that are in an unphosphorylated state. exception of STAT-2 differentially bind more than 10 Cytokine stimulation induces phosphorylation of tyr- related g-activated sequence elements that are charac- osine residues on the receptor that serve as docking sites terized by the consensus sequence, TTNCNNNAA for STATs via their SH2 domains. Once bound to the (Horvath et al., 1995; Xu et al., 1996). (A complex receptor, all members of the STAT family become comprising STAT1, STAT2 and IRF9 binds to the IFN- tyrosine phosphorylated in response to cytokine stimu- a/b-stimulated response element, AGTTN3TTTC;re- lation at a conserved C-terminal tyrosine, Y694 for viewed in O’Shea et al., 2002.) The linker domain example, in the case of STAT-5. Phosphorylation of this functions as a spacer to maintain proper conformation tyrosine appears to be achieved by growth factor between the dimerization and DNA-binding domains. receptors as well as by JAK and Src kinases, depending The SH2 domain, which is highly conserved among the on the nature of the cell type and the ligand/receptor STATs, plays a very important role in STAT signaling interactions. This form of phosphorylation induces being critical for the recruitment of STATs to activated STAT homo- and heterodimerization via the interaction receptor complexes and for the interaction with JAK of the SH2 domain of one STAT molecule with the and Src kinases. In addition, it is required for STAT phosphotyrosine residue of another. Once phosphorylated, the dimerized STATs are then able to translocate to the nucleus. In addition to tyrosine phosphorylation, Coiled- several STATs are regulated by serine phosphorylation N-terminalcoil DNA-bindingLinkerSH2 Transactivation at a conserved PSMP motif, which is located in the Stat1 pYpS transactivation domain. C-terminal serine phosphorylation is stimulated by several cytokines and is mediated by serine/threonine kinases including but not limited to extracellular responsive kinase, p38, JNK and protein kinase C-d and positively regulates the transactivation Stat2 pY potential of these proteins (reviewed in Khwaja, 2006). Kovarik et al. (2001) demonstrated that the specificity of signaling by STAT-1 depends on SH2 and C-terminal Stat3 pYpS domains that regulate Ser727 phosphorylation, thereby differentially affecting specific target gene expression. It is known that complete activation of STAT-1 requires phosphorylation at both Y701 and S727. Interestingly, Stat4 pYpS S727 phosphorylation of STAT-1 in IFN-g-treated mouse fibroblasts occurred without a need for p38 mitogen-activated protein kinase (MAPK), extracellular responsive kinase-1 and -2 or JNK, and required both Stat5a pYpS an intact SH2 domain and phosphorylation of Y701. In contrast, ultraviolet-induced STAT-1 phosphorylation on S727 required p38 MAPK, but no SH2 domain– phosphotyrosine interactions. Mutation of S727 differ- Stat5b pYpS entially affected IFN-g target genes, at the level of both basal and induced expression. Furthermore, S727 of STAT-3 is phosphorylated in response to stimuli that differ from those for STAT-1 S727, and transfer of the Stat6 pY STAT-3 C terminus to STAT-1 changed the pathway specificity of STAT-1 Ser727 phosphorylation to that of Figure 4 Structure of STAT proteins. STATs harbor six domains, STAT-3. This series of experiments shows that STAT C the N-terminal, coiled-coil, DNA-binding, linker, SH2 and termini contribute to the specificity of cellular responses transactivation domains. The N-terminal and DNA binding by linking individual STATs to different kinase path- domains cooperate in binding to the promoters of target genes. Regulatory phosphotyrosine (pY) and phosphoserine residues (pS) ways and doing so through an intrinsically different are also shown. STAT, signal transducers and activators of requirement for serine phosphorylation at different transcription. target gene promoters.

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6730 Cytokine signaling and signal transducers and activators stimulation, whereby the same STATs are activated and of transcription activation by Janus kinases and Src endogenous c-Src associates with and mediates the family kinases activation of STAT-3. Taken together, these results suggest that Src family Because the cytokine receptor–ligand interactions result kinases mediate the phosphorylation of STAT-3 in the activation of JAKs, which often exist in mediated by IL-3R interactions and play a critical role association with cytokine receptors, and because this in signal transduction pathways associated with myeloid activation is obligatory for the activation of STATs, it is cell proliferation. These results also suggest that widely accepted that STATs are substrates for JAKs. activation of STAT-3 following cytokine stimulation This notion is supported by early studies such as that of of certain hematopoietic cells might follow a very Flores-Morales et al. (1998), which showed in vitro different pathway from that seen with STAT-5. Whereas phosphorylation of purified STAT-5 by JAK2. This one or both isoforms of STAT-5 interact directly with study also showed STAT-5 in its non-phosphorylated JAK2, which in turn mediates their phosphorylation, form was able to form a stable complex with activated STAT-3 activation might require its interaction with JAK2, whereas non-activated JAK2 and phosphory- c-Src, which in turn mediates its phosphorylation lated STAT-5 were unable to participate in complex (Chaturvedi et al., 1998). Based on these results, a formation. A second line of evidence, which suggests second model of STAT activation has been proposed, that JAKs are activators of STATs, stems from the use where JAKs may be more crucial to phosphorylation of of dominant-negative mutants. Overexpression of domi- cytokine/growth factor receptors. Moreover, JAK- nant-negative JAK1 and TYK2 mutants can suppress mediated phosphorylation may create docking sites on transcriptional activation of a reporter gene downstream the receptors for binding of SH2-containing proteins from an IFN-a/b-stimulated response element and such as STATs, Src kinases and other signaling inhibit STAT-1 and -2 phosphorylation (Krishnan intermediates (Reddy et al., 2000). JAKs or Src kinases, et al., 1997). depending on the nature of STAT that is being In spite of these and other studies, activated JAKs do activated, then induce tyrosine phosphorylation and not seem to exhibit specificity for a particular STAT, activation of STAT proteins (Figure 3). as different receptors activate a common STAT even The notion that different STATs might be phos- though they activate distinctively different JAKs (Dar- phorylated by different tyrosine kinases under different nell, 1997; Kohlhuber et al., 1997). In addition, chimeric conditions is supported by studies with other tyrosine receptor molecules that harbor different JAK-binding kinases. Examination of the molecular mechanisms sites but the same STAT-binding site can activate the associated with v-Abl-mediated transformation shows same STAT (Kotenko et al., 1996; Kohlhuber et al., that B cells transformed by this oncogene exhibit 1997). Thus, the specificity for STAT phosphorylation constitutively activated forms of JAK1, JAK3 as well appears to be determined by the docking sites for as STAT-1, -3 and -5 (Danial et al., 1995, 1998). STATs that are present in the receptors themselves. Activated JAK1 in these cells was found to be associated The notion that STATs are activated by kinases other with the v-Abl protein. In addition, a dominant-negative than JAKs was at first supported by indirect evidence. mutant of JAK1 was found to inhibit STAT activation For example, IL-3 stimulation leads to activation of mediated by v-Abl, suggesting that the v-Abl protein JAK2 and phosphorylation as well as activation of activates STATs via activation of JAK1. It is also STAT-5a and -5b, and mutational studies have shown interesting to note that a C-terminal deletion mutant of that JAK2 is essential for STAT activation (Caldenho- IL-3bc, termed bc541, was found to be deficient in its ven et al., 1995; Mui et al., 1995a, b; Kouro et al., 1996; ability to activate STAT-5, while still being able to Matsuguchi et al., 1997; Smith et al., 1997). However, a activate JAK2 (Smith et al., 1997). These observations C-terminal mutant of the bc-subunit has been described also imply that while JAK2 activation is a critical step in that can activate JAK2 but is unable to activate STAT- IL-3/-5/GM-CSF-mediated activation of their cognate 5, indicating that activation of JAK2 alone is not receptors, it is by itself not adequate for STAT sufficient for STAT-5 activation (Smith et al., 1997). activation. In sharp contrast, the BCR-ABL oncogene A role for Src kinases in STAT activation was first constitutively activates STAT-1 and -5, with very little suggested by studies aimed at investigating the mole- or no effect on the activation of JAKs (Carlesso et al., cular mechanisms associated with Src-mediated trans- 1996; Frank and Varticovski, 1996; Ilaria and Van formation. v-Src-transformed NIH3T3 cells Etten, 1996; Nieborowska-Skorska et al., 1999) Unlike constitutively express tyrosine-phosphorylated STAT-3 v-Abl-transformed B cells, overexpression of dominant- (Yu et al., 1995; Cao et al., 1996) and in vitro studies negative JAK mutants in these cell lines had no effect on have shown that v-Src can bind to and phosphorylate STAT phosphorylation (Ilaria and Van Etten, 1996). STAT-3 (Cao et al., 1996). Similarly, v-Src-transformed Similarly, Philadelphia chromosome-positive K562 cells 32Dcl3 myeloblastic cells constitutively express phos- express constitutively activated STAT-5 and overexpres- phorylated forms of STAT-1, -3 and -5 in the absence of sion of a dominant-negative STAT-5 suppresses their cytokine (Chaturvedi et al., 1997). In this model, STAT- transformed state. 3 activation is blocked by a dominant-negative mutant Another line of evidence comes from the early study of Src, but not that of JAK-2 (Chaturvedi et al., 1998). of Kazansky et al. (1999), who studied the DNA binding These events mirror the signaling events induced by IL-3 and tyrosine phosphorylation of STAT-5a and -5b

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6731 following PRL stimulation or Src activation. Their positive regulation of prosurvival genes, STAT-3 also results show that following PRL activation, both STAT- appears to regulate genes important for cell-cycle 5a and -5b were rapidly phosphorylated and translo- regulation, which include MYC and cyclin D1. It also cated to the nucleus. Src activation resulted in the same promotes angiogenesis and invasion by directly binding phenotype. While overexpression of a dominant-nega- to the promoters of the vascular endothelial growth tive mutant of JAK2 prevented PRL-induced tyrosine factor and matrix metalloproteinase-2 genes, respec- phosphorylation and nuclear translocation of STAT-5a tively. In addition to upregulating the growth-promot- and -5b, expression of dominant-negative JAK2 had no ing genes, STAT-3 has also been found to negatively effect on the Src-mediated phosphorylation of STATs. regulate death-inducing genes such as tumor necrosis Instead, there was a modest increase in the levels of Src- factor (Niu et al., 2001). STAT-5 behaves similarly in mediated phosphorylation of STAT-5. These studies that it too regulates the expression of Bcl-2 family again suggest that there exist two independent pathways members (such as Bcl-xL) and proliferation-associated that mediate STAT activation, one that is dependent on genes such as c-myc, cyclin D2 and pim-1 (reviewed in JAKs and the other that is dependent on Src kinases. Haura et al., 2005). However, it is important to note that The context of the cytokine and cell type appears to play regulation of target gene expression by both of these a critical role in determining as to which pathway is STATs may not overlap with respect to tissue type and utilized by the cell. stimulus. Table 2 provides a partial list of some STAT-1, -3 and -5 target genes.

Targets of signal transducers and activators of transcriptions Other pathways activated by cytokines

The number of STAT responsive genes is vast. However, IL-3 as well as a number of other cytokines activate depending on the specific STAT protein that is multiple signal-transduction pathways, including the expressed and the cell type in which it is expressed, the Ras and PI3K pathways. Upon IL-3 stimulation, the nature of the target genes that are repressed and/or adaptor molecule Shc is rapidly phosphorylated and activated can vary or be remarkably similar. For associates with the phosphorylated bc-subunit of the IL- example, IFN-g, via STAT1, induces an ‘interferon 3R. IL-3 stimulation also results in tyrosine phosphor- signature’ that is common among cell types and includes ylation of the inositol phosphatase (SHIP), which forms genes such as Irg47, Ifi202 and 204, Irf1 and ISG15. a complex with Shc, Grb2 and Sos. Upon recruitment, STAT1 appears to have tumor-suppressive properties Shc binds to the phosphorylated Y577 of the bc-subunit and, as such, it has been shown to positively regulate the and subsequently interacts with the adaptor protein expression of caspases and negatively regulate that of Grb2, which in turn associates with mSos, a nucleotide antiapoptotic Bcl-2 family genes (reviewed in Alvarez exchange factor for Ras. This is followed by the and Frank, 2004; Haura et al., 2005). It has also been activation of Ras and c-Raf as well as the subsequent shown to bind to the STAT-responsive element located downstream activation of the MAPKs, extracellular within the p21 (CDKN1A) known to negatively regulate responsive kinase-1, -2 and p38. Activation of this the kinase activity of CDK2, an important enzyme that cascade culminates in the increased expression of mediates cell-cycle progression (Bromberg et al., 1996; transcription factors c-fos and c-jun (reviewed in Reddy Chin et al., 1996). et al., 2000) and the activation of STATs. STAT However, other STATs, such as STAT-3, -5 and -6, proteins serve as substrates for MAPKs whereby the regulate genes in a more cell-type restrictive manner, conserved C-terminal serine residue in their transactiva- whereby the set of genes that is induced in response to a tion domains is phosphorylated by MAPKs (Wen et al., given cytokine differs from one cell type to the next 1995; Zhang et al., 1995; Jain et al., 1998; David et al., (reviewed in Murray, 2007). STAT-3 and -5 have both 1995a, b) and protein kinase C (Jain et al., 1999; been shown to play key roles in cellular transformation Gartsbein et al., 2006), thus enhancing their transcrip- and hence it is not surprising that these proteins regulate tional activity. the expression of genes that control processes such as IL-3/IL-5 and GM-CSF also induce a rapid activation proliferation, apoptosis and angiogenesis. Depending on of the lipid kinase PI3K. Interestingly, the same region the cell type and cytokine, STAT3 regulates the of the bc-subunit that is responsible for the activation of expression of genes such as the Bcl-2 family, survivin the Ras pathway seems to be involved in signaling via and Fas and suppresses apoptosis. In a myeloma model, PI3K. PI3K associates with the bc-subunit and this IL-6-mediated activation of STAT-3 results in the interaction may be influenced by the adaptor protein upregulation of Bcl-xL, while similar activation of p80. The p80 adaptor protein acts as a scaffold that STAT-3 in T lymphocytes results in the transcriptional interacts with the bc chain, the p85 subunit of PI3K and upregulation of Mcl-1, another member of the Bcl-2 Src kinases in IL-3-stimulated cells. Downstream family. STAT-3 has also been shown to bind to the proteins recruited by the PI3K pathways upon IL-3 promoter of the Survivin gene, a member of the stimulation include AKT. PI3K-dependent activation of inhibitors of apoptosis (IAP) family, and upregulate its protein kinase B/AKT in response to IL-3 stimulation expression (Gritsko et al., 2006). In addition to the has been observed in multiple cells lines and these

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6732 Table 2 Target Genes of STAT-1, -3 and -5 (SHPs), SHP1 (perviously termed PTP1C) and SHP2 STAT Gene (previously termed PTP1D). Each is characterized by the presence of two SH2 domains in addition to a STAT1 Bcl-xL C-terminal phosphatase catalytic domain. SHP1 is Bcl-2 primarily expressed in hematopoietic cells, while the bFGF CIITA expression pattern of SHP2 is more ubiquitous. These Caspase-1 proteins, which act via association of their SH2 domains Caspase-2 with phosphotyrosine residues, have been shown to Caspase-3 dephosphorylate both activated cytokine receptors and Caspase-7 JAKs that have been recruited to receptor complexes. c-myc mcp-1 Dephosphorylation of receptors also prevents their MMP-9 association with STATs and thus this represents an MMP-2 indirect method of STAT inhibition (reviewed in p21 Valentino and Pierre, 2006). Loss of phosphotyrosine residues to which SHP1 binds on the Epo, IL-3, -5 and STAT3 Bcl-xL Bcl-2 GM-CSF receptors results in sustained JAK activation cdc25a (Yi et al., 1993; Klingmuller et al., 1995), although c-myc SHP2 has been reported to function as both a positive cyclin A and negative regulator of cytokine receptor signaling cyclin D1 cyclin D2 (reviewed in Neel et al., 2003). SHPs have also been cyclin D3 shown to bind JAKs directly and mediate their depho- Fas sphorylation (David et al., 1995a, b; Jiao et al., 1996; HIF-1a Haque et al., 1998; Migone et al., 1998). Detailed IL-6 Mcl-1 analysis has revealed that SHP2 is tyrosine phosphory- survivin lated by JAK1 and JAK2 but not by JAK3, on Y304 MMP-2 and Y327 via direct association. The SHP-2 and JAK MMP-9 association does not require the SH2 domain of SHP2 Pim-1 or the JH2 domain of JAKs, but does require the Pim-2 p21 N-terminal region of JAK proteins and regions encom- Survivin passing amino-acid residues 232–272 on the SHP2 VEGF protein. Interestingly, SHP-2 phosphatase activity seems to be non-essential for JAK–SHP2 interactions, as STAT5 Bcl-xL Bcl-2 mutations that render SHP2 inactive do not abolish c-myc the interaction between SHP2 and JAKs. Cyclin D1 The second phosphatase that negatively regulates Cyclin D2 JAK–STAT signaling is the transmembrane PTPase Cyclin D3 CD45, which is highly expressed in all hematopoietic Cyclin E Pim-1 lineages at all stages of development and is a key regulator of antigen receptor signaling in T and B cells. Abbreviations: HIF, hypoxia inducible factor; IL, interleukin; MMP, Although Src family kinases were identiﬁed as primary matrix metalloproteinase; STAT, signal transducers and activators of molecular targets for CD45, targeted disruption of the transcription; VEGF, vascular endothelial growth factor. CD45 gene leads to enhanced cytokine and IFN receptor-mediated activation of JAKs and STAT proteins. In vitro, CD45 directly dephosphorylates and studies suggest a role for this pathway in the transmis- binds to JAKs and negatively regulates IL-3-mediated sion of cell-survival signals in response to IL-3 (reviewed cellular proliferation, Epo-dependent hematopoiesis, in Reddy et al., 2000; Figure 4). IFN-mediated antiviral responses (Irie-Sasaki et al., 2001) and IL-4/anti-CD40-induced switch recombination (Yamada et al., 2002). Phosphotyrosine phosphatase 1B and T-cell protein Negative regulation of Janus kinases–signal transducers tyrosine phosphatase (TC-PTP) share sequence simila- and activators of transcription signaling rities in their catalytic domains and comprise the third group of phosphatases that regulate JAK–STAT signal- Negative regulation by protein tyrosine phosphatases ing. Phosphotyrosine phosphatase 1B is localized to the Protein tyrosine phosphatases (PTPs) regulate the endoplasmic reticulum and is expressed in several tissues. activities of kinases and other proteins by depho- TC-PTP, on the other hand, is primarily expressed in sphorylating tyrosine residues (reviewed in Pallen hematopoietic cell types and exists in two forms due to et al., 1992). Three types of PTPs have been shown to alternative splicing. p45 (TC45 or TC-PTPa) is localized negatively regulate JAK–STAT pathways. The ﬁrst to the nucleus, whereas the longer p48 isoform (TC48 or phosphatases that demonstrated a regulatory role in TC-PTP1b) is cytoplasmic. Phosphotyrosine phospha- this pathway are the SH2-containing phosphatases tase 1B and TC-PTP proteins recognize tyrosine residues

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6733 in the JAK activation loop although the specificity for SOCS proteins, such as SOCS1 and SOCS3, possess a surrounding residues differs. Hence, JAK2 and TYK2 kinase inhibitory region that is believed to compete with are physiological substrates of phosphotyrosine phos- substrates of JAKs (reviewed in Khwaja, 2006) and phatase 1B (Myers et al., 2001), whereas JAK1 and peptides that correspond to this region can function as JAK3 are substrates for TC-PTP (Simoncic et al., 2002). SOCS1 antagonists (Waiboci et al., 2007). TC-PTPa has also been shown to inactivate STAT-1, The third way in which SOCS proteins inhibit JAK– STAT-3 (ten Hoeve et al., 2002) and STAT-6 (Lu et al., STAT pathways is by promoting ubiquitination and 2007). subsequent proteasome-mediated degradation of JAKs. SOCS proteins function as part of an E3 ubiquitin ligase complex and in vitro, SOCS1 has been shown to target Negative regulation of Janus kinases by suppressors of JAK2 for ubiquitination (Ungureanu et al., 2002). cytokine signaling family proteins The CIS (cytokine-induced SH2 containing proteins)/ Negative regulation of signal transducers and activators SOCS (suppressors of cytokine signaling)/STAT-in- of transcriptions by protein inhibitor of activated duced STAT inhibitor/JAK-binding protein family of STAT proteins proteins possess SH2 domains that allow protein– Protein inhibitor of activated STAT (PIAS) family protein interactions with members of the cytokine proteins were originally described as negative regulators receptor family and other signaling components. of STAT signaling but have since been shown to exhibit Although this family has members with many diverse activity toward a variety of transcription factors. These names, they are commonly referred to as SOCS proteins. proteins contain an N-terminal LXXLL co-regulator The SOCS proteins, which were cloned simulta- motif, a zinc-finger domain and a C-terminal acidic neously by several independent groups, are small domain. There are five PIAS proteins (PIAS1, PIASx, proteins that possess central SH2 domains and con- PIAS3a and -b, PIASy), and all bind to activated STAT served C-terminal SOCS/CIS boxes (Endo et al., 1997; dimers and inhibit STAT-mediated transcription by Naka et al., 1997; Starr et al., 1997). CIS, the first distinct mechanisms. PIAS1 and PIAS3 associate with identified member of the family, was cloned as an early STAT-1 and -3, respectively, and directly inhibit DNA response gene for IL-2, IL-3 and Epo and was found to binding. PIASx interacts with STAT-4, although it and be associated with these receptors (Yoshimura et al., PIASy act by a different mechanism whereby they 1995; Matsumoto et al., 1997; Verdier et al., 1998). regulate the recruitment of transcriptional repressors Moreover, overexpression of CIS led to a suppression of such as histone deacetylases (HDAC’s) to the promoters signaling in response to IL-3 and Epo. SOCS1 (also of their target genes (reviewed in Rakesh and Agrawal, known as SSI1 or JAK-binding protein) was later 2005; Khwaja, 2006). Recent studies have demonstrated identified as a potent inhibitor of JAKs (Endo et al., that some PIAS family members possess small ubiqui- 1997; Naka et al., 1997; Starr et al., 1997). Interestingly, tin-like modifier E3-ligase activity and mediate the SOCS genes for CIS, SOCS1, -2 and -3 are rapidly sumoylation of STATs (Ungureanu et al., 2003, 2005). upregulated at the transcriptional level following cyto- This form of protein modification is similar to ubiqui- kine stimulation (Starr et al., 1997), and the presence of tination but does not promote degradation. Rather, it g-activated sequence elements in their promoters sug- has been shown to alter subcellular localization and gests that their expression is regulated as part of a protein–protein interactions, which alter protein activity negative-feedback loop (reviewed in Valentino and and stability. Pierre, 2006). To date, there are eight members of the SOCS family, CIS and SOCS1–7. (SOCS proteins, with the exception Other forms of negative regulation of SOCS4, have more than one name) (reviewed in Krebs Recently, an E3 ubiquitin ligase was isolated that targets and Hilton, 2001).Taken together, there are three general STAT proteins for proteasome-mediated degradation. methods by which these proteins regulate JAK–STAT This protein, termed SLIM (Tanaka et al., 2005), activity. The first is by competing with JAKs and STATs mediates the degradation of STAT-1 and -4 and for binding to receptors. As mentioned above, CIS is enhances their dephosphorylation. In addition to specific associated with several cytokine receptors, including the protein families that bind to and regulate JAKs and Epo receptor. In this case, CIS binds to the STAT-5 STATs directly, there are other mechanisms by which binding site of the receptor (at Y401), prevents STAT-5 cytokine receptor signaling is inhibited. Cells often binding and inhibits STAT-5-mediated signaling (Yoshi- express soluble forms of receptors that compete with mura et al., 1995). SOCS5 also associates with the IL-4R their membrane-bound counterparts and compete for and inhibits JAK1-mediated signaling by a similar ligand binding, and membrane-bound receptors can also mechanism (Seki et al., 2002). undergo endocytosis (reviewed in Kisseleva et al., 2002). The second method by which SOCS proteins negatively regulate JAK–STAT signaling is by binding to JAKs directly. SOCS1, via its SH2 domain, binds to Conclusion and future directions Y1007 in the activation loop of JAK2. Originally identified as negative regulators of IL-6 signaling (Starr It is becoming increasingly evident that the interaction et al., 1997), subsequent studies have revealed that some of cytokines with their receptors leads to the activation

Oncogene JAKs and STATs in cytokine signaling SJ Baker et al 6734 of multiple signal-transduction pathways, which can be induced by cytokines has shed light on how STAT extraordinarily similar, even for different cytokines. In proteins function. Similarly, the JAK2V617F mutation spite of what appears to be an ‘overlap’ in pathways, that is present in other myeloproliferative disorders has each cytokine elicits different biochemical and biological revealed the importance of the JAK pseudokinase responses, even those cytokines that share the same domain and the requirement of cytokine receptors in signal-transducing receptor unit. JAKs and STATs are JAK activation. Future studies in these rapidly evolving key players in this process, and a detailed understanding areas will undoubtedly continue to reveal more in- of how they transduce signals will go a long way toward formation about JAKs and STATs and how tumor cells enabling us to develop targeted therapies that are exploit them to induce disease. speciﬁc for these protein families. For example, it has been known for about a decade that certain STATs are Acknowledgements constitutively activated by BCR-ABL, the oncoprotein expressed in Philadelphia chromosome-positive chronic This work was supported by grants from the National myelogenous leukemias. A comparison of the simila- Institutes of Health (5RO1HL080666-02) and the Department rities between this form of STAT activation versus that of Defense (W81XWH-06-1-0267) to EPR.

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