View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Magazine R760

Primer superfamily is the utilization of following type I and II shared subunits receptor oligomerization, including – a single receptor chain may the MAPK (mitogen-activated participate in the generation of the , also known as ERK functional receptor complex for for extracellular-signal-regulated signalling multiple different ligands. As such, kinase) cascade, the JAK/STAT the superfamily can be subdivided pathway (/signal into receptors sharing the common transducer and activator of Christian A. J. Voβhenrich and β chain, the common γ chain, the transcription), and the PI3-K James P. Di Santo gp130 molecule, the IL-20Rβ chain (phosphoinositide 3-kinase) and the IL-22Rα chain (see Table cascade. The JAK/STAT pathway are low molecular 1). In addition, a number of appears uniquely coupled to type I weight proteins produced by receptor chains are shared by two and II cytokine receptor signaling, leukocytes that bind to cell different -binding receptor and has been the subject of surface receptors and act in an complexes: the IL-4Rα, the IL-7Rα, considerable analysis: the current autocrine and/or paracrine the IL-12Rβ1, the IL-10Rβ and the model is depicted in Figure 1. fashion. These secreted factors IL-20Rα chain. Homodimerization, hetero- modify the cell differentiation Receptor subunit oligo- dimerization or heterotrimerization program (survival, proliferation, merization plays an essential role of receptor chains in the presence maturation, induction of or in signaling via the type I and II of ligand (Table 1) generates a protection from apoptosis) of the cytokine receptors. The activation signaling-proficient complex, target cells to which they bind. As of multiple, distinct intracellular which brings together the such, interleukins impact on cascades has been documented receptor-bound JAKs. JAK diverse biological processes: tissue growth and repair, Table 1. The type I and II cytokine receptors. hematopoietic homeostasis, and Type Ligands Receptor JAK STAT Inhibitora at multiple levels of the host γ γ defense against pathogens. It is I c-dependent: c + ligand-specific 1,3 5,3 CIS (IL-2), IL-2, 7, 9, receptor chain, except SOCS1 (IL-2), therefore not surprising that the 15, 21 IL-2R and IL-15R which SOCS3 (IL-2,9) rather generic designation use IL-2Rβ plus a ‘interleukin’ does not refer to a specific α-chainb γ homogeneous family of proteins, IL-4 Type I IL-4R, c + 1,3 6 SOCS1,3 but instead to groups of proteins IL-4Rα ; type II IL-4R, IL-4Rα + IL-13Rα that adopt different three- β β c-dependent: c + ligand-specific 2 5 CIS (IL-3), dimensional structures, bind to IL-3, 5, GM-CSF receptor chain, SOCS1 (IL-3), distinct classes of receptors, and only βc binds JAK SOCS3 (IL-3) initiate unique gp130-dependent: 1,2,Tyk2 3 SOCS1,2 (IL-6,LIF), pathways. Our discussion of IL-6, 11, OSM, SOCS3 (IL-6,11,LIF) interleukins will be structured CNTF, LIF, CT-1 β β according to the two main classes IL-12 (p35/p40) IL-12R 1, IL-12R 2 2,Tyk2 4 IL-23 (p19/p40) IL-12Rβ1?4 of receptors to which they bind: IL-27 (p28/EBI3) WSX-1 the type I and type II cytokine TSLP TSLPR, IL-7Rα – 5 SOCS1 receptor families and the IL- GH GHR homodimer 2 5 CIS, SOCS1,2,3 1R/TLR (interleukin-1 receptor/ EPO EPOR homodimer 2 5 CIS, SOCS3 Toll-like receptor) superfamily. TPO TPOR homodimer 2 5 SOCS1,3 Prolactin PRLR homodimer 2 5 CIS, SOCS1,3 2 3 SOCS3 Type I and II cytokine receptor homodimer families G-CSF G-CSFR homodimer 2 3 (1,5) Type I cytokine receptors are II IFNα/β IFNα/βRα, β 1,Tyk2 1,2 SOCS1 transmembrane proteins with four IFNγ IFNγRα, β 1,2 1 SOCS1,3 conserved cysteine residues and a IL-10 IL-10Rα, IL-10Rβ 1,Tyk2 3 ND α β Trp-Ser-X-Trp-Ser (WSXWS) motif IL-22 (IL-TIF) IL-22R , IL-10R ? 1,3,5 ND IL-20 IL-22Rα, IL-20Rβ ?3ND in their extracellular domain, and a IL-20Rα, IL-20Rβ cytoplasmic tail containing IL-24 (MDA-7) IL-22Rα, IL-20Rβ consensus motifs (‘boxes’ 1 and 2) IL-20Rα, IL-20Rβ ?3ND involved in signal transduction. IL-19 IL-20Rα, IL-20Rβ ?3ND The type II cytokine receptors are The list includes the functional receptors for a given cytokine as well as the JAK/STAT mol- related but lack the extracellular ecules activated via the receptor. aPhosphatases and PIAS not taken into account. bIL-2Rα WSXWS motif (Table 1). Ligands and IL-15Rα are not chains. for these receptors belong to a GM-CSF, granulocyte/monocyte-colony-stimulating factor; TSLP, thymic stroma-derived lym- family characterized by the phopoietin; OSM, ; CNTF, ciliary neurotrophic factor; LIF, leukemia inhibitory factor; CT, cardiotrophin; GH, growth hormone; EPO, ; TPO, ; presence of four α helices. One γ β IFN, ; c, common cytokine receptor gamma chain; c, common cytokine receptor predominant characteristic of the beta chain; IL-TIF, interleukin-10-related T-cell-derived inducible factor; MDA, melanoma dif- type I and II cytokine receptor ferentiation-associated antigen; ND, not described. Magazine R761

A Ligand B Ras JAK JAK SOCS S P CIS T P S A T PIAS Raf T A T Shc P

JAK JAK Sos T S

P P T

P Grb2 A T A

P T Gab2 S P p85 P

S T S T

P

Shc T A A

P P T A T

S T PI3K S T A MAPK Nucleus T cascade PKB

Current Biology

Figure 1. Signal transduction via type I and type II cytokine and STAT proteins. (B) Pathways of Shc-mediated PKB and receptors. (A) Ligand-induced oligomerisation of receptor sub- MAPK activation and STAT-induced SOCS/CIS/PIAS inhibition. units leads to receptor phosphorylation thereby recruiting Shc See text for details. autophosphorylation, as well as (Figure 1). The adaptor molecule multiple Grb2 proteins thereby receptor tyrosine phosphorylation Grb2 plays a major role in initiating organizing and potentiating the (Figure 1) generates specific the MAPK cascade. Upon receptor signals by the activated receptor; docking sites for adaptor proteins binding, Grb2 recruits, via its in this way, adaptors serve as a containing Src homology 2 (SH2) amino-terminal SH3 domain, the core for building multiple signaling domains or phosphotyrosine- guanine nucleotide exchange pathways in parallel. binding (PTB) domains for factor Sos to the plasma The regulation of signaling building an intracellular signaling membrane where it activates the through type I and II cytokine scaffold. STAT proteins bind to GTPase Ras, which in turn receptors occurs at multiple levels: the receptor via SH2 domains, activates MAPK/ERK, via several soluble forms of ligand-binding and themselves become tyrosine intermediate kinases. Activation of receptor subunits may act to phosphorylated. The the MAPK/ERK pathway is not sequester extracellular ligands phosphorylated STAT proteins specific to the type I and II under some conditions; then dissociate from the receptor, cytokine receptors and the competition for shared receptor homodimerize or heterodimerize substrates of the activated MAPKs subunits can decrease the (again via their SH2 domains), and are diverse, including transcription efficiency of signaling; and tyrosine translocate into the nucleus where factors and other kinases. phosphatases (including SHP-1, they stimulate target gene The MAPK cascade is just one SHP-2, and CD45) may act to transcription (Figure 1). of several pathways involved in dampen formation or stability of Four JAKs (JAK1, JAK2, JAK3 signaling from Grb2. While the intracellular signaling complexes. and Tyk2) and six STAT proteins amino-terminal SH3 domain of Suppressor of cytokine signaling (STAT1–6) have been identified in Grb2 binds to Sos, its carboxy- (SOCS) proteins are a family of mammalian cells. Curiously, no terminal SH3 domain recruits, molecules that can bind activated simple rules apply to the probably at the same time, the JAKs or phosphorylated receptor utilization of the different JAKs Gab1 or Gab2 adaptor proteins. chains and thereby impede and STATs with different These proteins are phosphoryl- docking of STATs and/or adaptor receptors. Involvement of different ated and serve as docking sites molecules. Different SOCS JAK and STAT proteins in signal for other proteins, such as the p85 proteins are induced by different transduction pathways from type I subunit of PI3-K, the . The SOCS family and II cytokine receptors may be phosphorylation of which leads to includes eight members: cytokine- highly specific or promiscuous the activation of the protein inducible SH2-domain-containing (Table 1). kinase B (PKB) pathway (Figure 1). protein (CIS) and SOCS1–7, which As mentioned above, the Some cytokine receptors, for all contain a protein motif JAK/STAT pathway is an example IL-7Rα, have direct designated the SOCS box, also important, but by no means the binding sites for the SH2 domain found in a number of proteins only, signal transduction pathway of the p85 subunit of PI3-K, unrelated to cytokine signaling. triggered by type I and II cytokine thereby allowing direct stimulation A different family of inhibitors — receptors. Recruitment of SH2- or of this specific pathway. protein inhibitors of activated STAT PTB-domain adaptors to the Scaffolding proteins like Shc also (PIAS) — has been recently phosphorylated receptor chains bind to phosphorylated receptor described to bind activated STAT can result in the activation of the chains and become proteins and prevent their MAPK and the PI3-K pathways phosphorylated. Shc can recruit dimerization (Figure 1). Current Biology Vol 12 No 22 R762

AB CD E IL-1 TRAF6

IL-1 IL-1 Ig

Ig MAP3K Ig Ig TAK1? MKK6?

?

Ig Ig

P TIR TIR ?

IL-1R IL-1RAcP OLLIP IKK complex MAPK cascade T

DD

TIR DD DD DD

IκB

DD DD IRAK TRAF6 DD IRAK4 κ MyD88 NF B activation Current Biology

Figure 2. Signal transduction via the IL-1 receptor. (A) Building of complex to the receptor. (C) Autophosphorylation and subsequent the signaling-proficient receptor–ligand complex consisting of IL- dissociation of IRAK–IRAK4. (D) Binding of TRAF6 by 1, IL-1R1 and IL-1RAcP allows for the recruitment of MyD88 via IRAK–IRAK4. (E) TRAF6-mediated activation of NF-κB and MAPK, the TIR domain. (B) Recruitment of the TOLLIP–IRAK–IRAK4 probably via TAK1 and MKK6, respectively. See text for details.

The IL-1R/TLR superfamily dimensional structures and bind associated factor 6 (TRAF6; Recent discoveries within the to the same receptors, they have Figure 2). TRAF6 in turn activates IL-1/IL-1R family provide a almost identical biological the MAPKKKs TAK1 and MKK6 dynamic example of how rapidly activities. Both IL-1 and IL-18 are and results eventually in the the field of interleukin research is generated as precursors, which activation of NFκB and the moving. Until recently, IL-1Rs are converted into mature forms MAPKs, JNK and p38 (Figure 2). were grouped in the family of Ig by caspase-1-mediated IL-1 function can be regulated (immunoglobulin-like)-domain proteolytic cleavage. IL-1β and IL- at multiple levels: ligand containing receptors on the basis 18 are only active as mature expression, and by modifying of the fact that they contain three proteins, while IL-1α is also active signaling through the IL-1R1 (such extracellular Ig domains. With the as a precursor. The binding of IL-1 as by phosphatases). In addition, characterization of the Toll to IL-1R1 is not sufficient for IL-1 function is regulated by two receptors, it became clear that a signaling; only after recruitment of distinct mechanisms at the level new superfamily could be defined, IL-1RAcP (IL-1R accessory of the : via based on a homologous protein, homologous to IL-1R1) is the IL-1 receptor antagonist cytoplasmic sequence — the the receptor complex signaling (IL-1ra), which inhibits recruitment Toll/IL-1R (TIR) domain — found proficient. IL-1R of IL-1RcAP; and via a ‘decoy’ not only in the Toll receptors, but heterodimerisation leads to the receptor, IL-1R2, which binds IL-1 also in the IL-1R. recruitment of MyD88 (Figure 2). and recruits IL-1RAcP but does The TIR-containing IL-1R/TLR Subsequently, a (probably) not initiate a signal transduction superfamily comprises three main preformed complex consisting of cascade due to its failure to subgroups: the IL-1R/IL-18R the recently discovered Toll- recruit MyD88. IL-1R2 can also be subfamily with their characteristic interacting protein (TOLLIP), proteolytically cleaved and extracellular Ig-domains; the Toll IL-1R-associated kinase (IRAK) subsequently sequester IL-1 in receptor family, whose members and IRAK4 is somehow recruited soluble form. possess an extracellular leucine- to the IL-1R–MyD88 receptor The structure and the signaling rich repeat (LRR); and a group of complex. The C2 domain of of the IL-18/IL-18R system are cytoplasmic proteins (for example, TOLLIP is believed to interact very similar to the IL-1/IL-1R the signaling molecule MyD88). with membrane lipids and may system. IL-18 binds to IL-18R As this review deals with play a role in the assembly of the (also known as IL-1R-related interleukin signaling, we will only signaling complex (Figure 2). protein 1), which then recruits the briefly consider the pathways Alternatively, since MyD88, IRAK IL-18RAP (IL-18R accessory described for the mammalian and IRAK4 each contain a death protein, also known as accessory IL-1R/IL-18R receptor family. IL-1 domain (DD), the proximity of protein-like). As the signaling and IL-18 are pro-inflammatory these molecules at the receptor through IL-18R appears to involve cytokines and are important may allow for their interaction the same molecules as described mediators in the activation of the through death domain association above for IL-1R, it is not surprising innate immune system. The term (Figure 2). Whatever the that IL-18 evokes similar IL-1 actually refers to two different mechanism, signaling involves biological responses as IL-1. molecules, IL-1α and IL-1β, which IRAK–IRAK4 Regulation of the IL-18/IL-18R have only 27% sequence identity autophosphorylation, its release system also occurs through at the DNA level. However, as they from the receptor complex and its binding of IL-18 by IL-18BP (IL-18 adopt very similar three- binding to TNF receptor binding protein). Magazine R763

Reconciling signaling pathways of the biological response(s) to significance of this cytokine with biological responses interleukins. redundancy? This is an important The term ‘cytokine redundancy’ If one interleukin can initiate question, since the concept of describes the in vitro observations different signal transduction cytokine redundancy evolved that diverse cytokines may elicit pathways, including their largely from in vitro studies. In similar biological effects on crosstalk, which pathways are contrast, clear cases of cytokine responding target cells. Two activated under physiological redundancy in vivo are lacking. observations regarding interleukin conditions and what dictates the Moreover, while some cytokines signaling appear relevant to this type of signal generated? The may appear to act in a redundant concept: first, receptor subunit answers to this question concern fashion, this does not necessarily sharing between distinct cytokine ‘availability’, ‘context’ and the demonstrate that all of the receptors (common β, common γ, ‘nature of the signal’. Availability biological effects of these gp130) provides an obvious means that in order to relay a different cytokines are redundant. mechanism to generate parallel signal through a specific pathway, We favor the notion that the in intracellular signals. Second, certain conditions must be met vivo role for interleukins is highly different subfamilies of cytokine (such as necessary adaptor specific and much more restricted receptors can initiate similar or proteins must expressed, docking than suggested by previous in identical signal transduction sites for the adaptor proteins vitro studies. With continued pathways (PI3-K, MAPK). It is also must be accessible, potential generation of mice carrying apparent that a given cytokine second messengers must be conditional mutations in receptor is capable of converting present in a certain concentration interleukins and their receptors, a ligand-binding event into and so on). Context characterizes the true biological roles for these different signal transduction the state of the cell (immature or families of molecules should be pathways. This second mature, naive or memory, revealed. These discoveries will characteristic of cytokine receptor activated or resting) that is about have an important impact on the signaling may provide clues to to respond to a given ligand as use of interleukins under diverse understanding ‘cytokine well as the nature of other signals clinical conditions, including pleiotropy’, which describes the perceived by that cell at the same autoimmunity, immunodeficiency capacity of single cytokines to time. Lastly, ‘nature of the signal’ and for modulating immune elicit multiple biological effects. signifies the strength and duration responses against pathogens. While these proposed molecular of the signal: a short exposure to mechanisms provide reasonable a certain stimulus may allow the Further reading replies to the questions of receptor to relay the signal to only Cantley, L.C. (2002). The cytokine redundancy and one pathway, while a prolonged phosphoinositide 3-kinase pathway. Science 296, 1655–1657. pleiotropy, there are some exposure may culminate in the Dong, C., Davis, R.J. and Flavell, R.A. reported observations which activation of several pathways. Of (2002). MAP kinases in the immune suggest that interleukin signal course, these different conditions response. Annu. Rev. Immunol. 20, 55–72. integration may be more complex. have to be considered as a whole Downward, J. (2001). The ins and outs Mutational analysis of cytokine and not as unrelated entities. of signalling. Nature 411, 759–762. receptor chains has identified There are examples where Gadina, M., Hilton, D., Johnston, J.A., Morinobu, A., Lighvani, A., Zhou, regions critical for certain certain biological endpoints Y.J., Visconti, R. and O’Shea, J.J. biological responses in vitro; for appear clearly associated with (2001). Signaling by type I and II example, STAT activation was activation of specific signaling cytokine receptors: ten years after. found to be essential for cell events. Cell survival induced by Curr. Opin. Immunol. 13, 363–373. γ Greenhalgh, C.J. and Hilton, D.J. proliferation induced by IL-2 or interleukins utilizing the common (2001). Negative regulation of growth hormone or prolactin, chain appear to act via induction cytokine signaling. J. Leukoc. Biol. whereas mutations affecting and/or stabilization of expression 70, 348–356. O’Neill, L.A. and Dinarello, C.A. (2000). docking of other adaptors had of Bcl-2 family members. The IL-1 receptor/toll-like receptor little effect. In contrast, use of Curiously, this does not appear to superfamily: crucial receptors for pharmacological agents be the case for survival signals inflammation and host defense. demonstrated that interleukin- induced through receptors with Immunol. Today 21, 206–209. Rane, S.G. and Reddy, E.P. (2002). induced lymphocyte proliferation intrinsic activity JAKs, STATs and Src kinases in is sensitive to selective inhibition (c-, Flk2/Flt3). It is not evident hematopoiesis. Oncogene 21, of the p38 MAPK pathway. Thus why two distinct classes of 3334–3358. Suzuki, N., Suzuki, S., Duncan, G.S., the paradigm ‘single pathway – cytokine receptors use divergent Millar, D.G., Wada, T., Mirtsos, C., single response’ may be an mechanisms to achieve a similar Takada, H., Wakeham, A., Itie, A., oversimplification, especially if biological effect. Li, S. et al. (2002). Severe impairment of interleukin-1 and certain biological responses Additional questions in the Toll-like receptor signaling in mice require integrative activation biology of interleukin signaling lacking IRAK-4. Nature 416, across multiple pathways. remain unanswered. Multiple 750–756. ‘Crosstalk’ refers to the capacity distinct cytokines have been Unité des Cytokines et Développement of individual signaling pathways to shown to elicit similar in vitro Lymphoïde, Institut Pasteur, 25 rue du influence each other, and biological responses in target Dr Roux, 75742 Paris, France. E-mail: probably allows for the fine tuning cells — what is the physiological [email protected]