gp130 gp130 gp130
FIGURE 7-23 Structure of cytokine receptors. A, Receptors for different cytokines are classified into families on the basis of conserved extracellular domain structures and signaling mechanisms. The cytokines or other ligands that bind to each receptor family are listed below the schematic drawings. WSXWS, tryptophan-serine-X-tryptophan-serine. B, Groups of cytokine receptors share identical or highly homologous subunit chains. Selected examples of cytokine receptors in each group are shown.
are chemotactic cytokines, activate a large subfamily of receptors and have been discussed in Chapter 3. Chemo-kine receptors are seven-transmembrane GPCRs described in the early part of this chapter and are not elaborated on here.
Type I Cytokine Receptors (Hematopoietin Receptor Family)
Type I cytokine receptors are dimers or trimers that typically consist of unique ligand-binding chains and one or more signal-transducing chains, which are often shared by receptors for different cytokines. These chains contain one or two domains with a conserved pair of cysteine residues and a membrane proximal peptide stretch containing a tryptophan-serine-X-tryptophan-serine (WSXWS) motif, where X is any amino acid (Fig. 7-23A). The conserved sequences of the receptors form structures that bind cytokines that have four a-helical bundles and are referred to as type I cytokines, but the specificity for individual cytokines is determined by amino acid residues that vary from one receptor to another. This receptor family can be divided into subgroups based on structural homologies or the use of shared signaling poly-peptides (Fig. 7-23B). One group contains a signaling component called the common y chain (CD132); in this group are the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. A distinct subgroup of type I receptors includes receptors that share a common P chain (CD131) subunit. This subgroup includes the receptors for IL-3, IL-5, and GM-CSF. Another subgroup of receptors uses the gp130 signaling component, and this includes the receptors for IL-6, IL-11, and IL-27. All the type I cytokine receptors engage JAK-STAT signaling pathways.
Type II Cytokine Receptors (Interferon Receptor Family)
The type II receptors are similar to type I receptors by virtue of possessing two extracellular domains with conserved cysteines, but type II receptors do not contain the WSXWS motif. These receptors consist of one ligand-binding polypeptide chain and one signal-transducing chain. All the type II cytokine receptors, like the type I receptors, engage JAK-STAT signaling pathways. This family includes receptors for type I and type II interferons and for IL-10, IL-20, and IL-26.
These receptors are part of a large family of preformed trimers (some of which are not considered cytokine receptors) with conserved cysteine-rich extracellular domains and shared intracellular signaling mechanisms that typically stimulate gene expression but in some cases induce apoptosis. Some important receptors of this family, most of which will be discussed in other chapters in their biologic contexts, include the TNF receptors TNFRI and TNFRII, the CD40 protein, Fas, the lymphotoxin receptor, and the BAFF receptor family. The ligands for these receptors also form trimers. Some of these ligands are membrane bound, whereas others are soluble.
Binding of the ligands to the preformed trimeric receptors typically induces a conformational change and recruits adaptor proteins to the receptor complex. These adaptors in turn recruit enzymes that include both E3 ubiquitin ligases, which mediate nondegradatory polyu-biquitination, and protein kinases, which initiate downstream signaling. In the case of the TNF receptor illustrated in Figure 7-24, the receptor recruits the adaptor protein TRADD (TNF receptor-associated death domain), and TRADD in turn can recruit proteins called TRAFs (TNF receptor associated factors), which possess a unique type of E3 ligase activity that will be discussed in the section on NF-kB signaling. The type I TNF receptor (there are two different receptors for TNF) and Fas (CD95) can also recruit adaptors that induce the activation of caspase-8, and these receptors, in certain cells, can thereby induce apoptosis.
Cross-linking of TNF-R1 by TNF
Binding of adaptor protein (TRADD)
Binding of signaling intermediates (TRAF, RIP, FADD)
"Death domain" TRADD
Generation of active transcription factors (AP-1, NF-kB)
"Death domain" TRADD
Activation of effector caspases
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