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C H A P T E R 16

CYTOKINE/RECEPTOR FAMILIES AND SIGNAL TRANSDUCTION

Montaser Shaheen and Hal E. Broxmeyer

CYTOKINE/RECEPTOR FAMILIES AND SIGNAL organization and use intracellular signaling mediators of the Janus
kinase (JAK) and signal transducer and activator of transcription
TRANSDUCTION (STAT) families. In this regard type I and II cytokine receptors repre-
sent a homogeneous structural group of proteins. However, sequence
Cytokines are secreted biologically active molecules that regulate cell homology is observed in a limited number of cases, such as for the
growth and metabolism and cellular interactions through their specific GH/prolactin (PRL) family and for the IL-6 family. Nonetheless,
binding to defined receptors and the subsequent induction of intracel- evidence of the common derivation of cytokines can be observed in
lular signaling. Cytokines are classified based on the primary structural the common four-helix bundle structure, in addition to the similar
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features of the extracellular domains of their receptors. Most of what intron-exon relationship and the clustering observed for certain
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is known of cytokine actions and their intracellular signaling is based cytokine genes such as genes of the IL-4 family. The receptors can
on the effects of purified natural or recombinant cytokines on either a be composed of dimers of a single chain (granulocyte-CSF receptor
factor-dependent cell line or an isolated population of primary target (G-CSFR), EPO receptor (EPOR), TPO receptor (c-MPL), or can
cells. It is however, becoming clear that cytokines can be functionally be heterodimeric with a common signaling subunit and a unique
modified in vivo by specific enzymes, and these modifications, which ligand-binding chain. These heterodimeric receptors can be grouped
are not usually taken into consideration when analyzing intracellular into families based on whether they share the common β-chain
signaling can elicit different signaling events. Moreover, it has also (granulocyte–macrophage [GM]-CSFRα, IL-3Rα, IL-5Rα), or those
recently become clear that removing cells from the body for analysis that share the gp130 receptor (IL-6Rα, leukemia inhibitory factor
can change their metabolism and activity, and perhaps how these cells (LIF) receptor β, ciliary neurotrophic factor receptor α, IL-11Rα
may signal in response to intact or enzyme-truncated cytokines. IL-12R, IL-23R, oncostatin M receptor α, Ciliary Neurotrophic Factor
Class or type I cytokines (often referred to as hematopoietins) Rα [NTFRα]) and those that share the common γ-chain (IL-2Rα,
regulate development, differentiation, and activation of hematopoi- IL-2Rα, IL-4Rα, IL-7Rα, IL-9Rα, IL-13Rα, IL-15Rα and IL-21Rα;)
etic and immune cells. Their receptors are type I membrane proteins (see Fig. 16.1). Cytokine binding triggers receptor homodimerization
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with an N-terminal extracellular and C-terminal intracellular orienta- (e.g., G-CSFR ) or heterodimerization/oligomerization of receptor
tion. Type I cytokine receptors include those for colony stimulating subunits (e.g., GM-CSFR) or it induces a conformational change in
factors (CSFs), interleukins (ILs), erythropoietin (EPO), thrombo- preformed receptor dimers (EPOR) resulting in the activation of the
poietin (TPO) (Fig. 16.1), and hormones such as growth hormone JAKs (Fig. 16.4). Unlike other receptors with intrinsic enzyme activity
(GH) and leptin. (e.g., receptor tyrosine kinases [RTK] such as Flt3 and c-Kit), most
Class II cytokines consist of type I interferons (IFNs), which cytokine receptors are constitutively associated with kinases. These
include 16 members that are produced by almost every nucleated cell cytoplasmic kinases comprise the four members of the JAK family:
with approximately 20% to 60% sequence identity including 12 JAK1, JAK2, and Tyk2, which bind to a wide range of receptors,
subtypes of IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω. Type I IFNs whereas JAK3 binds to only one receptor, the common gamma chain
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initiate signaling by binding to the same receptor composed of two (γc). This binding is mediated by interactions between the 4.1, ezrin,
subunits called IFNAR1 and IFNAR2. Type II IFN consists of the radixin, moesin (FERM) domain of JAK (Fig. 16.5), and the Box 1
single IFN-γ, which signals through a heterodimeric receptor com- membrane proximal intracytoplasmic region of the receptor. Upon
posed of IFNGR1 and IFNGR2. Type III IFNs include IFN-λ1 ligand binding, JAKs come into juxstapositioning and phosphorylate
(IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B). Some place the themselves and their associated receptors. Mutagenesis studies have
IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26) shown that there are distinct regions of individual phosphorylated
within this group. Type III IFN receptor is composed of IL-10Rß receptors that transmit signals for cell survival, proliferation, differ-
and IL-28R (Fig. 16.2). entiation, and/or activation via interaction with adaptor molecules.
The structural similarities of type I cytokines were not initially Phosphorylation of certain residues generates docking sites for the
recognized. Cloning of their receptors, however, revealed significant Src homology 2 (SH2) domains of the STATs. Once bound to the
homology in that the extracellular regions contain a common domain receptor/JAK complex, STATs themselves become phosphorylated,
with four conserved cysteines (C4) in the N-terminal segment and which induces a conformational change that generates active STAT
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a tryptophan-serine doublet near the C-terminal end. Mutagenesis dimers via reciprocal phosphotyrosine and SH2 domain interaction
studies revealed an essential structural role for these amino acids (see Fig. 16.4). The dimers translocate to the nucleus, where they
in maintaining the tertiary structure of the receptor without being bind to DNA sequences in the promoters of target genes to activate
involved in cytokine interactions. There is a 200 amino acid region transcription.
evolutionarily derived from a tandem of two ancestral fibronectin-like Other posttranslational modifications beside tyrosine phosphory-
domains, which has been named the hematopoietin receptor domain lation occur. These include acetylation, sumoylation and ubiquity-
or cytokine-binding homology region (CHR) because it mediates lation that modulate cytokine signaling through modifying
the interactions with cytokines. The α receptors of IL-2 and IL-15 protein-protein or protein-DNA interactions and protein stability.
of the γc family are atypical cytokine receptors in that they do not Multiple mechanisms exist to attenuate cytokine signaling, which
contain a CHR, but rather they contain sushi domains. Two conserved ensures controlled cellular responses to cytokines and prevents
Box 1/Box 2 regions are located in the proximal intracytoplasmic pathologic hyperactivation. Because the signaling is mediated by
segment (Fig. 16.3). By contrast, type II cytokine receptors contain extensive phosphorylation, phosphatases have emerged as important
two cysteine doublets (C2-C2) located in the C-terminal end of both negative regulators. Examples of these include the SH2 containing
fibronectin-derived domains. They retain Box 1/2 regions but lack phosphatase (SHP) proteins. Other regulators have been identified
the tryptophan-serine-x-serine-tryptophan motif. Both types of recep- including protein inhibitors of activated STAT (PIAS), suppressor
tors bind ligands that display common spatial four α-helix bundle of cytokine signaling (SOCS) proteins and cytokine inducible

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