Oncogene (2000) 19, 2557 ± 2565 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes

Sergei V Kotenko1 and Sidney Pestka*,1,2

1Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08854-5635, USA; 2Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey, NJ 08901, USA

Cells of the immune system communicate with each other between coagulation factor VIIa (FVIIa) and tissue to initiate, establish and maintain immune responses. The factor (TF), which belongs to the class II cytokine communication occurs through cell-to-cell contact or receptor family and may mediate signaling, will also be through a variety of intercellular mediators that include discussed. Other aspects of these receptors have also been cytokines, chemokines, growth factors and hormones. In recently reviewed (Domanski and Colamonici, 1996; the case of cytokines, the signal is transmitted from the Kirchhofer and Nemerson, 1996; Pestka et al., 1997a; outside to the inside of a cell through cell surface Carmeliet and Collen, 1998; Mogensen et al., 1999). receptors speci®c for each cytokine. At this step the The class II cytokine receptor family consists of signal is also decoded and ampli®ed: ligand binding seven members with known function: tissue factor, causes recruitment and/or activation of numerous three pairs of two receptor subunits of the receptor cytoplasmic proteins. One cytokine can activate a complexes for either type I (IFN-a, IFN-b, IFN-o,and number of signal transduction pathways leading to IFN-t) and type II (IFN-g) IFNs and IL-10. In regulation of a wide array of biological activities. One addition, there are currently two orphan receptors of these pathways, the Jak-Stat pathway, is brie¯y CRF2-8 and CRF2-9 (Kotenko and Pestka, unpub- reviewed here with respect to the class II cytokine lished data; Lok et al., 1999a,b). The extracellular receptors. Signal transduction through receptors for domains of the class II receptors have tandem interferons Type I (IFN-a,IFN-b, IFN-o) and Type II ®bronectin type III (FNIII) domains. Most known (IFN-g), and interleukin 10 (IL-10) is described in detail. family members have two tandem FNIII domains, In addition, a complex between tissue factor (TF) and although a subunit of the type I IFN receptor complex coagulation factor VIIa, and two new receptors related (IFN-aR1) has four tandem domains (Figure 2). The to the class II cytokine receptor family are discussed. structures of the soluble extracellular domains of tissue Oncogene (2000) 19, 2557 ± 2565. factor and one subunit of the type II IFN receptor complex (IFN-gR1) have been determined (Harlos et Keywords: cytokines; interleukin-10; interferons; recep- al., 1994; Walter et al., 1995; Banner et al., 1996). Their tors; IFN-8; IFN-a intracellular domains vary in length and do not demonstrate any similarity in their primary structures. Four receptor chains, IFN-aR1, IFN-aR2, IL-10R2 and IFN-gR2 are clustered on human chromosome 21 The Jak-Stat signal transduction pathway is activated by (Jung et al., 1987; Lutfalla et al., 1990, 1993, 1995; many polypeptide ligands. The initial event leading to Langer et al., 1990; Soh et al., 1993,1994a,1994b; the signaling cascade is the binding of a ligand to its Reboul et al., 1999). IFN-aRI has also been designated speci®c cell surface receptor. Two cytokine receptor the a-chain (IFN-aRa) comparable to other cytokine families, class I and class II, are primarily utilized by receptor chains that bind ligand. It should be noted ligands inducing the Jak-Stat pathway. These two that for many receptor complexes, two or more chains families are characterized by their patterns of conserved can contribute to ligand-binding so that naming a ®rst amino acid residues within the receptor extracellular ligand-binding component the a-chain may be fraught domains (Bazan, 1990; Thoreau et al., 1991). The class I with erroneous implications. Furthermore, because the family has numerous members; cytokines utilizing these genetic nomenclature for human and mouse genes does receptors activate a number of signal transduction not permit use of Greek letters, the designation of pathways beside the Jak-Stat pathway. Whereas there components with Greek letters immediately requires are fewer class II family members, they are more speci®c that the gene be designated by a di€erent abbreviation in their choice of signal transduction pathways: so far, than the protein. Thus, the recommended numerical they tend to prefer Jak-Stat signaling over other nomenclature was derived with these notions in mind pathways. Cytokine signaling through class II receptor and provides abbreviations where the genes and the complexes (Figure 1) is the subject of this review. proteins use the same alliteration. For additional Speci®cally, receptor complexes for type I and type II details of nomenclature see (Pestka et al., 1997a). interferons (IFNs) and interleukin-10 (IL-10) and their Two receptor chains, IFN-gR1 and CRF2-8, map to ligand-induced signal transduction events will be brie¯y Chr. 6 (Rashidbaigi et al., 1986; Lok et al., 1999a), two reviewed in this article. In addition, a distinct complex chains, TF and CRF2-9, are encoded on Chr. 1 (Carson et al., 1985; Lok et al., 1999b) and the IL- 10R1 chain is encoded on Chr. 11 (Taniyama et al., *Correspondence: S Pestka, Cancer Institute of New Jersey, 195 1995). Members of the Jak family of tyrosine kinases Little Albany Street, New Brunswick, New Jersey, NJ 08901, USA associated with these receptors have been identi®ed in a Cytokine class II receptors SV Kotenko and S Pestka 2558 number of studies and information about Stat reviews Pestka et al., 1987, Pestka, 1997b; Moore et al., recruitment sites is also summarized (Figure 1 and 1993). Table 1). The orphan receptor chains (CRF2-8 and Both IFN-g and IL-10 are homodimers and their CRF2-9) possess classical Stat3 recruitment sites crystal structures have been reported (Ealick et al., (YXXQ) and likely a Jak1 association site (Stahl et 1991; Walter and Nagabhushan, 1995; Zdanov et al., al., 1995; Usacheva et al., 2000). 1995). They have signi®cant homology in their tertiary Ligands utilizing class II cytokine receptors for structures despite the lack of signi®cant homology signaling, namely IFNs and IL-10, are important between their primary structures. Thus, it was not immunomodulators able to induce a broad variety of surprising that, when the receptor chains for these biological responses depending on the cell type and ligands were identi®ed, the structure of the functional speci®c conditions and/or additional costimulators. IFN-g and IL-10 appeared to be similar although they Type I IFNs, which include the family of IFN-as, utilize distinct receptor subunits for signaling (Figures IFN-b, and IFN-o, are initial vital signals for cells and 3 and 4) and subsequently activate distinct but the immune system to initiate an antiviral response. overlapping combinations of Jak and Stat proteins. IFN-g and IL-10 are primarily involved in regulation Although the crystal structure of only one ligand- of speci®c immune responses, promoting (driving receptor complex of this family of receptors, IFN-g and toward) TH1orTH2-like responses, respectively (see soluble IFN-gR1, has been reported (Walter et al.,

Figure 1 Class II cytokine receptor family. IL-10R1 and IL-10R2 are two subunits of the IL-10 receptor complexes (Lutfalla et al., 1993; Liu et al., 1994; Kotenko et al., 1997). IFN-gR1 and IFN-gR2 are two subunits of the IFN-g receptor complex (Aguet et al., 1988; Soh et al., 1994a). IFN-aR1 and IFN-aR2 are two subunits of the type I IFN receptor complex; IFN-aR2 has two membrane bound splice variants, IFN-aR2c with longer intracellular domain and IFN-aR2b with shorter intracellular domain (Uze et al., 1990; Novick et al., 1994; Domanski et al., 1995; Lutfalla et al., 1995). Only IFN-aR2c (IFN-aR2 shown in the Figure) is thought to be competent for Jak and Stat recruitment and signaling. Tissue factor (TF) is a receptor for coagulation factor VIIa (FVIIa) (Scarpati et al., 1987; Fisher et al., 1987; Spicer et al., 1987; Morrissey et al., 1987). Orphan receptors CRF2-8 and CRF2-9 are also diagramed and the `?' means the ligand for them has not been identi®ed (Kotenko and Pestka, unpublished data; Lok et al., 1999a,b). Jak members associated with the intracellular domains of the receptors and Stat members recruited directly or indirectly (in parentheses) through these receptors are shown. The dashes indicate these receptors do not recruit Stats or associated with Jaks. The `3?' and `Jak1?' means we predict that Stat3 and Jak1, respectively, recruited to the receptor chain based on the structure of the intracellular domain. Chromosomal locations of the receptors are also shown. The number of amino acid residues comprising the extracellular (signal peptide), transmembrane and intracellular domains of the receptors is shown for each of the receptor chains

Table 1 Class II cytokine receptors Ligand IFN-a IFN-g IL-10 FVIIa ? ?

Receptor chains IFN-aR1 IFN-aR2 IFN-gR1 IFN-gR2 IL-10R1 IL-10R2 TF CRF2-8 CRF2-9 Chromosomal location 21 21 6 21 11 21 1 6 1 Stats ± 1, 2, 3 1, (3) ± 3, (1) ± ± 3? 3? Jaks Tyk2 Jak1 Jak1 Jak2 Jak1 Tyk2 ± Jak1? Jak1? Receptor chains are as indicated in the legend for Figure 1. Chromosomal locations of human receptor chains are shown. Jak members associated with the intracellular domains of the receptors and Stat members recruited directly or indirectly (in parentheses) through these receptors are shown. The dashes indicate the intracellular domains of these chains do not recruit Stats and/or Jaks, as noted in the Table. The `?' means the ligand has not been identi®ed; and `3?' and `Jak1?' means we predict that Stat3 and Jak1, respectively, recruited to the receptor chain based on the structure of the intracellular domain

Oncogene Cytokine class II receptors SV Kotenko and S Pestka 2559

Figure 2 Alignment of amino acid sequences of the extracellular domains of class II cytokine receptors. Full length extracellular domains with signal peptides are shown for both chains of the IFN-g and IL-10 receptor complexes, IFN-gR1 and IFN-gR2, and IL-10R1 and IL-10R2, respectively, for the second chain of the IFN-a receptor complex, IFN-aR2, for TF and for two orphan receptors, CRF2-8 and CRF2-9. The extracellular domain of the IFN-aR1 chain is divided into two segments: signal peptide and N- terminal D200 domain comprise IFN-aRln and the C-terminal D200 is designated here IFN-aR1c

1995), the common architecture of the IL-10 and IFN- contrast, the Jak2 negative g2A cells expressing a g receptor complexes suggests that IL-10 and IFN-g kinase negative Jak2 mutant do not respond to IFN-g signaling involve the same basic events (Figures 3 and (Briscoe et al., 1996). After the phosphorylation of the 4). Both ligands are homodimers which bind to two R1 intracellular domains occurs, Stats are then molecules of their respective ligand binding receptor recruited to the receptor complexes based on speci®c chains (the IFN-gR1 or IL-10R1 chains or R1; also interaction of Stat SH2 domains with appropriate designated Ra chains) which also serve as the signal phosphotyrosine motifs within the R1 intracellular transducing (Stat recruiting) receptor chains. But these domains. The R2 intracellular domains do not possess events alone are not sucient for signaling. The model Stat recruitment or docking sites and thus do not (Figures 3 and 4) illustrates that the binding of the participate in the Stat recruitment process. The Stats ligand homodimers to the R1 chains results in are then phosphorylated on Tyr residues resulting in formation of a non-functional intracellular receptor homo- or heterodimer formation, dissociation from complex as previously demonstrated (Rashidbaigi et receptors and nuclear translocation. In the nucleus the al., 1986; Jung et al., 1987, 1988, 1990). The second Stat dimers bind to speci®c regions of promoters of chains (the IFN-gR2 or IL-10R2 chains, or R2 chains; cytokine-responsive genes and participate with other also designated Rb chains) are required to assemble an transcriptional factors, enhanceosomal and transcrip- active intracellular receptor complex and thus to tosomal proteins and other factors (Schaefer et al., initiate the signal transduction events (Figures 3 and 1995; Halle and Meisterernst, 1996; Bhattacharya et 4) (Kotenko et al., 1995, 1996, 1997, 1999). The al., 1996; Zhang et al., 1996; Horvai et al., 1997; Carey, intracellular domains of both the IFN-g and IL-10 R1 1999; Gall et al., 1999; Pollack et al., 1999; Paulson et chains are associated with Jak1, whereas the second al., 1999; Nakashima et al., 1999; Zhang et al., 1999). chains bring to their respective complexes distinct Jak These complexes then modulate the ®nely-tuned and family members associated with the R2 intracellular well-orchestrated transcription of cytokine-regulatable domains. The IFN-gR2 chain associates with Jak2 and genes. the IL-10R2, with Tyk2. Ligand-induced oligomeriza- The combinations of Stats activated by IFN-g and tion of receptor components results in Jak activation IL-10 are distinct and in some aspects opposing. IFN-g leading to phosphorylation of the R1 intracellular triggers Stat1 and, in some cases, dependent on the cell domains on Tyr residues. The functions of di€erent type, speci®c conditions and/or ratio of receptor Jaks in the various receptor complexes are not subunits expressed, a small amount of Stat3 (Shuai et equivalent. For example, the Jak1 negative U4A cells al., 1992; Horvath et al., 1995; Sato et al., 1997; expressing a kinase negative Jak1 mutant exhibit some Caldenhoven et al., 1999; Kotenko et al., 1999). In activities in response to IFN-g, indicating that Jak1 contrast, Stat3 and a small amount of Stat1 are predominantly plays a structural role in the IFN-g activated during IL-10 signaling (Finbloom and Wine- receptor complex rather than a catalytic role. In stock, 1995; Wehinger et al., 1996; Kotenko et al.,

Oncogene Cytokine class II receptors SV Kotenko and S Pestka 2560

Figure 3 Model of the cytokine class II receptor complexes and signal transduction. A and B. IFN-g (a) or IL-10 (b) homodimers bind to their ligand binding R1 chains. The corresponding second chains (helper or accessory receptors IFN-gR2 or IL-10R2, Kotenko et al., 1996, 1997, 1999) are then recruited to the complexes to initiate signal transduction events in the Jak-Stat pathway. Stats are recruited through the ligand binding chains (signal transducing receptors, Kotenko et al., 1996). IFN-a (c) binding to the subunits of the type I IFN receptor complex, the IFN-aR2c and the IFN-aR1 chains, initiates the cascade of signal transduction events. All Stats involved in IFN-a signaling are activated through the intracellular domain of the IFN-aR2c chain (Kotenko et al., 1999). Signal transduction events activated upon binding of FVIIa (d) to TF are not well de®ned

Figure 4 Model of the IFN-g and Epo receptor complexes. (a) represents the active heteromeric IFN-g receptor complex with two IFN-gR1 and two IFN-gR2 subunits per complex. The IFN-g homodimer binds to two IFN-gR1 chains, followed by its interaction with two IFN-gR2 chains. The association with receptor subunits Jak1 and Jak2 kinases (or other members of the Jak family substituting for Jak2) activate one another by transphosphorylation initiating the signaling cascade. JAS, represents Jak association site; SRS, Stat recruitment site; ST, signal transducing receptor; AC, accessory chain receptor; PTK, protein tyrosine kinase; gR2/X, chimeric receptor with the extracellular domain of the IFN-gR2 and the intracellular domains of various receptors swapped for the intracellular domain of the Hu-IFN-gR2 chain (Kotenko et al., 1996). (b) represents the IFN-gR1 homodimer bound to IFN-g. The cytoplasmic domains of the two chains are too far apart to permit transactivation of the two Jak1 kinases. (c) depicts the EpoR/gR1 homodimer which, unlike the IFN-gR1 homodimer, permits transactivation of the two Jak1 molecules

Oncogene Cytokine class II receptors SV Kotenko and S Pestka 2561 1997). A single phosphotyrosine motif (YDKPH) shorter cytoplasmic domain than the IFN-aR2c chain. within the IFN-gR1 chain is responsible for Stat1 All these variant forms have the same extracellular recruitment (Greenlund et al., 1994). Stat3 can be domain and bind the ligands. However, only the IFN- recruited to the tyrosine-phosphorylated IL-10R1 aR2c chain, which has the longer cytoplasmic domain, intracellular domain through the interaction with two seems to function in signaling. The IFN-aR1 chain Stat3 docking sites (Weber-Nordt et al., 1996). exhibits a distinct structural feature not present in Mechanisms of Stat3 activation by IFN-g as well as other members of cytokine receptor class II family: its Stat1 activation by IL-10 have not been delineated. extracellular domain is twice the size of the extra- One possibility is that Stat1 or Stat3 can be activated cellular domains of other members of this family, in cells through activated Stat3 or Stat1, respectively; having four tandem FNIII domains rather than two. alternatively, the detection of the small amount of The IFN-aR1 chain binds most type I IFNs weakly at activated Stat1 by IL-10 or Stat3 by IFN-g does not best, but modulates the di€erential recognition of type occur in cells and might be an artifact of the EMSA. I IFNs by the IFN-aR2/IFN-aR1 complex (Cutrone In this context it is interesting to note that IFN-g and Langer, 1997). A soluble complex of human IFN-b and IL-10 act antagonistically, particularly in the with the extracellular domains of the IFN-aR1 and regulation of TH1 and TH2 dependent immune IFN-aR2 chains has an apparent stoichiometry of responses; in addition, macrophage activation by 1 : 1 : 1 (Arduini et al., 1999). All type I IFNs activate IFN-g is inhibited by IL-10 (Moore et al., 1993). A Jak1 and Tyk2 tyrosine kinases during signal transduc- number of mechanisms regulating this crosstalk can be tion leading to formation and activation of ISGF3 proposed. It is possible that both cytokines use a (IFN-a-Stimulated Gene Factor 3) DNA-binding similar approach to control T cells: the di€erential complexes consisting of Stat1 and Stat2 transcriptional expression of the IL-10 or IFN-g receptor second factors and p48 DNA-binding protein from the IFN chains in T cell subsets, as already shown in the case of regulatory factor (IRF) family of proteins (Fu et al., the IFN-gR2 chain (Pernis et al., 1995; Bach et al., 1990, 1992; Schindler et al., 1992; Veals et al., 1992; 1995; Sakatsume and Finbloom, 1996; Novelli et al., Velazquez et al., 1992; MuÈ ller et al., 1993). Jak1 is 1996; Skrenta et al., 1996). Alternatively, since Jak1 is associated with the IFN-aR2c intracellular domain activated by both ligands, if one of the R1 chains has a whereas the IFN-aR1 intracellular domain is associated higher anity site for Jak1 binding than the other R1 with Tyk2 (Colamonici et al., 1994; Domanski et al., chain, and if the amount of Jak1 is limited in a cell, 1997). Type I IFNs activate Stat1, Stat2 and Stat3 then the two receptor complexes may compete for Jak1 through the IFN-aR2c intracellular domain (Kotenko recruitment required for a functional receptor complex. et al., 1999; Nadeau et al., 1999). The IFN-aR1 Another possible mechanism may occur at the level of intracellular domain does not recruit Stats, but Stat activation. The heterodimeric Stat1:Stat3 complex supports type I IFN signal transduction by bringing may have a higher association constant than the Tyk2 tyrosine kinase to the receptor complex. How- Stat1:Stat1 homodimeric complex. In this scenario ever, the IFN-aR1 intracellular domain can modulate Stat3 will sequester activated Stat1 and prevent type I IFN signaling: the deletion of amino acids 525 ± formation of Stat1 homodimers. Thus, only when the 544 of the IFN-aR1 intracellular domain created a level of activated Stat1 exceeds the level of activated receptor which produced an enhanced response (Gibbs Stat3, are Stat1 homodimers formed and able to et al., 1996). initiate speci®c biological e€ects. These three receptor complexes de®ne a paradigm of It is also likely that a minimal level of Stat1 signaling for cytokines utilizing class II cytokine activation is required to induce biological e€ects. This receptors (Pestka et al., 1997a). Ligand binding induces may explain our previous observations that, despite the oligomerization of receptor subunits (Figures 3 and 4). fact that a small amount of Stat1 is activated by IL-10 The receptor chains can be divided into two classes: (1) or by modi®ed IFN-g receptor chains where the Stat1 the actual Signal Transducers (ST), containing Stat (or recruitment site is substituted by a Stat3 recruitment other SH2 domain containing protein) Recruitment site, the activation of Stat1 did not lead to activation Sites (SRS) and Jak Association Sites (JAS); and (2) of IFN-g speci®c biological activities (Kotenko et al., Accessory Chain (AC), containing only JAS, but no 1997, 1999). SRS. The higher anity ligand binding chains of the Less is known about the structure of the IFN-a/b/o receptor complexes of the class II cytokine receptor receptor complex. It is not certain whether type I IFNs family (IFN-gR1, IL-10R1 and IFN-aR2) are asso- interact with their receptor complex as monomers, ciated with Jak1 and, in addition, serve as the Stat dimers or trimers. It is likely that IFN-a interacts with recruitment chains. The primary function of the second the receptor as a monomer and IFN-b as a monomer chains of these receptors is to bring an additional or dimer (Pestka et al., 1983; Kempner and Pestka, tyrosine kinase to the receptor complexes, causing Jak 1986; Arduini et al., 1999). Two subunits of the type I cross-activation and initiation of signal transduction IFN receptor complex were identi®ed: Hu-IFN-aR1 (Kotenko et al., 1995, 1996, 1997, 1999; Bach et al., and Hu-IFN-aR2 and its variants (Figures 1 and 3). 1996). The second chains do not recruit Stats. The The major ligand binding chain is the Hu-IFN-aR2 intracellular domains of the AC can be swapped with chain (Novick et al., 1994; Domanski et al., 1995; the intracellular domains of other receptors. These Lutfalla et al., 1995; Cutrone and Langer, 1997). This substitutions bring other Jaks to the receptor com- receptor chain is expressed as three variants resulting plexes without a€ecting signaling. Thus, the particular from di€erential mRNA splicing. One, the Hu-IFN- Jak kinase recruited to the AC does not provide aR2a chain, is secreted, and the other two are speci®city for signal transduction (Figure 4). Only their membrane bound proteins with di€erent lengths of extracellular domains are speci®c for particular ligand their cytoplasmic domains: the IFN-aR2b chain with a receptor complexes. The Jaks show preferential

Oncogene Cytokine class II receptors SV Kotenko and S Pestka 2562 speci®city for association with the receptor intracellular residues within the IFN-gR1 involved in interaction domains, but the kinases per se are promiscuous and with IFN-g. Second, its ligand, the coagulation factor interchangeable for the Jak-Stat signal transduction FVII, is a serine/threonine protease, a very unusual pathway (Kotenko et al., 1996, 1997). ligand for cytokine receptors. It does not demonstrate Within the cytokine class I receptor family there are any structural similarity to either the IFNs or IL-10. cases where homodimerization of a single receptor Nevertheless, recent reports implicate induction of chain appears sucient for signal transduction. In certain biological activities in cells after binding of these instances, the receptor intracellular domain FVIIa to TF, suggesting the existence of signal contains all the JAS and SRS regions necessary and transduction events (Bromberg et al., 1995; Pendurthi sucient for signal transduction (as in the case of et al., 1997; Ollivier et al., 1998; Poulsen et al., 1998; EpoR, GHR or ProR2), the activation of a single Jak2 Cunningham et al., 1999; Camerer et al., 1999). While, is observed and a separate accessory chain is not there is no data demonstrating direct activation of the required (Argetsinger et al., 1993; Witthuhn et al., Jak-Stat pathway by TF:FVIIa complex, cells trans- 1993; Campbell et al., 1994; DaSilva et al., 1994; David fected with a reporter gene under control of the IFN-g- et al., 1994; Dusanter-Fourt et al., 1994; Rui et al., inducible promoter responded to FVIIa treatment by 1994). However, the Epo-induced homodimerization of upregulation of reporter gene expression, although the a chimeric protein with the EpoR extracellular domain authors suggested that MAP kinase activation was and the IFN-gR1 intracellular domain (EpoR/gR1) was responsible for FVIIa-induced transcription of a sucient for induction of IFN-g-like signaling (Figure reporter gene (Figure 3) (Poulsen et al., 1998). It is 4) (Muthukumaran et al., 1997). In contrast, the not clear how this unusual couple TF:FVIIa evolved so ligand-induced homodimerization of appropriate R1 far from the more classical cytokine class II ligand : subunits of the native IFN-g and IL-10 receptor receptor complexes. It is possible that TF plays role of complexes without subsequent recruitment of R2 the accessory chain, like R2 for the IL-10 or IFN-g subunits does not cause initiation of a signal transduc- receptor complexes or IFN-aR1 for the IFN-a receptor tion cascade (Figure 4). The explanation appears to complex, but acquired the ability to bind its ligand come from the geometry of the receptor complexes. FVIIa with high anity. However, the experiments When the crystal structure of the IFN-g:IFN-gR1 with chimeric receptors do not demonstrate the ability complex was solved (Walter et al., 1995) it became of the TF intracellular domain to associate with Jaks clear that, when one IFN-g homodimer binds two IFN- (Kotenko and Pestka, unpublished data). It remains to gR1 molecules, the two receptor subunits do not be seen whether the TF intracellular domain is interact with one another and are separated by 27AÊ responsible for initiation of signaling or whether there (Walter et al., 1995) at their closest point. Therefore, is an another yet unidenti®ed receptor subunit for though the IFN-gR1 chain possesses both a Jak1 FVIIa which transduces the signal alone or with the association site and a Stat1a-recruitment site, alone it is support of the TF intracellular domain. Two orphan unable to transduce a signal on homodimerization as class II receptors are possible candidates for an the two Jak1 kinases are not in physical proximity to FVIIaR2 chain. permit transphosphorylation. In contrast, GH- or Epo- When studied in greater detail, the Jak-Stat pathway, induced homodimerization of the GHR (de Vos et al., originally discovered as a seemingly simple straightfor- 1992) or the EpoR (Watowich et al., 1992) brings the ward pathway (ligand:receptor pair ? Jaks ? distinct intracellular domains of these receptors into close set of Stats ? speci®c biological e€ects), seems more proximity allowing interaction of receptor-associated and more complex with cross talk with other pathways. Jak2 molecules. Therefore, in the chimeric EpoR/gR1 Numerous divergent interacting partners of Jaks and dimer, two Jak1 kinases are brought suciently close Stats have been discovered revealing or just suggesting together to activate one another, albeit ineciently many new, unpredictable functions for Jaks and Stats (Figure 4) (Muthukumaran et al., 1997). (KlingmuÈ ller et al., 1995; Marrero et al., 1995; Thus the cytokine class II receptor complexes Yamauchi et al., 1997; Guillet-Deniau et al., 1997; possess a unique characteristic feature of the receptors Pollack et al., 1999, 2000). The Jak-Stat signal relative to the positioning of the Jaks. The geometry of transduction pathway has evolved, likely together with the receptor complexes is such that homodimerization cytokine families, from such lower eukaryotes as of their R1 chains yields a non-functional intracellular Dictyostelium discoideum (Adler et al., 1996; Kawata receptor complex. The accessory R2 chain completes et al., 1997; Araki et al., 1998). Along the evolutionary this function. We speculate that the presence of two path, it acquired many new alternative functions but distinct chains provides for more e€ective control and also retained at least partially, some original ancestral ®ne tuning of responses to ligand, and permits functions. Evolution from common ancestors may interactions with additional cellular components and, explain the fact that many cytokines activate an array possibly, multiple pathways. of overlapping functions (Fambrough et al., 1999). The However, it seems likely that at least one member of speci®city of cytokine signaling developed during the the cytokine class II receptor superfamily does not expansion of the pathway has only started to be follow the paradigm. Tissue factor, while a member of revealed. In spite of numerous elegant studies spot- the class II cytokine receptor family, stands far apart lighting certain aspects and mechanisms of the path- from the receptor complexes for IFNs and IL-10. The way, it seems likely that the Jak-Stat signaling network crystal structure of the FVIIa:TF complex has been is still far from being completely elucidated. solved and is very di€erent from that of the IFN- Many directions remain to be explored in the area of g:IFN-gR1 complex (Walter et al., 1995; Banner et al., cytokine class II receptors and signaling. Identi®cation 1996). First, the residues within the TF extracellular of new receptors and their ligand partners (Kotenko domain interacting with the FVIIa are distinct from and Pestka, unpublished data; Kotenko et al., 2000)

Oncogene Cytokine class II receptors SV Kotenko and S Pestka 2563 and at least one unusual receptor:ligand pair (TF, Acknowledgments FVIIa) requires a new perspective and, perhaps, some We thank Eleanor Kells for assistance in the preparation of additional missing elements. The solution of the the manuscript and Jerome Langer and Michael Newlon for structure of several ligand:receptor signaling complexes the critical review of the text. This study was supported in should help to extend the existing paradigm for part by American Heart Association Grant AHA#9730247N and by State of New Jersey Commission cytokine class II receptor complexes and signaling. on Cancer Research Grant#799-021 to SV Kotenko, and by United States Public Health Services Grants RO1- CA46465 and 1P30-CA72720 from the National Cancer Abbreviations Institute, RO1 AI36450 and RO1 AI43369 from the EpoR, Erythropoietin receptor; GHR, growth hormone National Institute of Allergy and Infectious Diseases and receptor; ProR, prolactin receptor. an award from the Milstein Family Foundation to S Pestka.

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Oncogene