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 cytokine shared cytokine receptor subunits receptor oligomerization, including – a single receptor chain may the MAPK (mitogen-activated participate in the generation of the protein kinase, also known as ERK Interleukin 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 (Janus kinase/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 Interleukins 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 ligand-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 signal transduction 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 Leptin Leptin receptor 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 type I cytokine receptor 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, oncostatin M; CNTF, ciliary neurotrophic factor; LIF, leukemia inhibitory factor; CT, cardiotrophin; GH, growth hormone; EPO, erythropoietin; TPO, thrombopoietin; presence of four α helices. One γ β IFN, interferon; 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 cytokines. 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.