Engaged Cytokine Receptors Activate Signaling Pathways

While some important cytokine receptors lie outside the class I and class II families, the majority are included within these two families. As mentioned previously, class I and class II cytokine receptors lack signaling motifs (e.g., intrinsic tyrosine kinase domains). Yet, early observations demon strated that one of the first events after the interaction of a cytokine with one of these receptors is a series of protein tyrosine phosphorylations. While these results were initially puzzling, they were explained when a unifying model emerged from studies of the molecular events triggered by binding of interferon gamma (IFN-7) to its receptor, a member of the class II family.

IFN-7 was originally discovered because of its ability to induce cells to block or inhibit the replication of a wide variety of viruses. Antiviral activity is a property it shares with IFN-a and IFN-p. However, unlike these other interferons, IFN-7 plays a central role in many immunoregulatory processes, including the regulation of mononuclear phagocytes, B-cell switching to certain IgG classes, and the support or inhibition of the development of TH-cell subsets. The discovery of the major signaling pathway invoked by interaction of IFN-7 with its receptor led to the realization that signal transduction through most, if not all, class I and class II cytokine receptors involves the following steps, which are the basis of a unifying signaling model (Figure 12-10).

■ The cytokine receptor is composed of separate subunits, an a chain required for cytokine binding and for signal transduction and a p chain necessary for signaling but with only a minor role in binding.

■ Different inactive protein tyrosine kinases are associated with different subunits of the receptor. The a chain of the receptor is associated with a novel family of protein tyrosine kinases, the Janus kinase (JAK) * family. The association of the JAK and the receptor subunit occurs spontaneously and does not require the binding of cytokine. However, in the absence of cytokine, JAKs lack protein tyrosine kinase activity.

■ Cytokine binding induces the association of the two separate cytokine receptor subunits and activation of the receptor-associated JAKs. The ability of IFN-7, which binds to a class II cytokine receptor, to bring about the association of the ligand-binding chains of its receptor has been directly demonstrated by x-ray crystallographic studies, as shown in Figure 12-11.

■ Activated JAKs create docking sites for the STAT transcription factors by phosphorylation of specific tyrosine residues on cytokine receptor subunits. Once receptor-associated JAKs are activated, they phosphorylate specific tyrosines in the receptor subunits of the

* The Roman god Janus had two faces. Kinases of the Janus family have two sites, a binding site at which they link with the cytokine receptor subunit and a catalytic site that, when activated, has protein tyrosine kinase activity. Some biochemists, wearied by the multitude of different protein kinases that have been discovered, claim JAK means Vust Another Kinase.

Dimerization of receptor

Dimerization of receptor

Tyrosine Kinase Phosphorylation

Activation of JAK family tyrosine kinases, phosphorylation of receptor

Tyrosine phosphorylation of STAT by JAK kinase

^rt Dimerization of STAT

Activation of JAK family tyrosine kinases, phosphorylation of receptor

Tyrosine phosphorylation of STAT by JAK kinase

^rt Dimerization of STAT

Janus Activated Kinase

Specific gene transcription

FIGURE 12-10

Specific gene transcription

FIGURE 12-10

General model of signal transduction mediated by most class I and class II cytokine receptors. Binding of a cytokine induces dimerization of the receptor subunits, which leads to the activation of receptor-subunit-associated JAK tyrosine kinases by reciprocal phosphorylation. Subsequently, the activated JAKs phosphorylate various tyrosine residues, resulting in the creation of docking sites for STATs on the receptor and the activation of the one or more STAT transcription factors. The phosphorylated STATs dimerize and translocate to the nucleus, where they activate transcription of specific genes.

complex. Members of a family of transcription factors known as STATs (signal transducers and activators of transcription) bind to these phosphorylated tyrosine residues. Specific STATs (see Table 12-2) play essential roles in the signaling pathways of a wide variety of cytokines. The binding of STATs to receptor subunits is mediated by the joining of the SH2 domain on the STAT with the docking site created by the JAK-mediated phosphorylation of a particular tyrosine on receptor subunits.

After undergoing JAK-mediated phosphorylation, STAT transcription factors translocate from receptor docking sites at the membrane to the nucleus, where they initiate the transcription of specific genes. While docked to receptor subunits, STATs undergo JAK-catalyzed phosphorylation of a key tyrosine. This is followed by the dissociation of the STATs from the receptor subunits and their dimerization. The STAT dimers then translocate into the nucleus and induce the expression of genes containing appropriate regulatory sequences in their promoter regions.

In addition to IFN-7, a number of other class I and class II ligands have been shown to cause dimerization of their receptors. An important element of cytokine specificity derives from the exquisite specificity of the match between cytokines and their receptors. Another aspect of cytokine specificity is that each particular cytokine (or group of redundant cyto-kines) induces transcription of a specific subset of genes in a given cell type; the resulting gene products then mediate the various effects typical of that cytokine. The specificity of cytokine effects is then traceable to three factors. First, particular cytokine receptors start particular JAK-STAT pathways. Second, the transcriptional activity of activated STATs

Interferon Gamma Jak Stat Pathway

FIGURE 12-11

The complex between IFN-7 and the ligand-binding chains of its receptor. This model is based on the x-ray crystallo-graphic analysis of a crystalline complex of interferon-7 (violet and blue) bound to ligand-binding a chains of the receptor (green and yellow). Note that IFN-7 is shown in its native dimeric form; each member of the dimer engages the a chain of an IFN-7 receptor, thereby bringing about receptor dimerization and signal transduction. [From M. R. Walter et al., 1995, Nature 376:230, courtesy M. Walter, University of Alabama.]

FIGURE 12-11

The complex between IFN-7 and the ligand-binding chains of its receptor. This model is based on the x-ray crystallo-graphic analysis of a crystalline complex of interferon-7 (violet and blue) bound to ligand-binding a chains of the receptor (green and yellow). Note that IFN-7 is shown in its native dimeric form; each member of the dimer engages the a chain of an IFN-7 receptor, thereby bringing about receptor dimerization and signal transduction. [From M. R. Walter et al., 1995, Nature 376:230, courtesy M. Walter, University of Alabama.]

STAT and JAK interaction with selected cytokine receptors during signal transduction

Cytokine receptor JAK

STAT and JAK interaction with selected cytokine receptors during signal transduction

Cytokine receptor JAK

STAT

IFN-7

JAK1 and JAK2

Stat1

IFN-a/ß

JAK1 and Tyk-2

Stat2

IL-2

JAK1 and JAK3

Stat5

IL-3

JAK2

Stat5

IL-4

JAK1 and JAK3

Stat6

IL-6

JAK1 (and sometimes others)

Stat3

IL-10

JAK1 and Tyk-2*

Stat3

IL-12

JAK2 and Tyk-2*

Stat4

*Despite its name, Tyk-2 is also a Janus kinase.

*Despite its name, Tyk-2 is also a Janus kinase.

SOURCE: Adapted from E. A. Bach, M. Aguet, and R. D. Schreiber, 1997, Annu. Rev. Immun. 15:563.

is specific because a particular STAT homodimer or het-erodimer will only recognize certain sequence motifs and thus can interact only with the promoters of certain genes. Third, only those target genes whose expression is permitted by a particular cell type can be activated within that variety of cell. That is, in any given cell type only a subset of the potential target genes of a particular STAT may be permitted expression. For example, IL-4 induces one set of genes in T cells, another in B cells, and yet a third in eosinophils.

released in chronic T-cell activation, is the best characterized. A segment containing the amino-terminal 192 amino acids of the a subunit is released by proteolytic cleavage, forming a 45-kDa soluble IL-2 receptor. The shed receptor can bind IL-2 and prevent its interaction with the membrane-bound IL-2 receptor. The presence of sIL-2R has been used as a clinical marker of chronic T-cell activation and is observed in a number of diseases, including autoimmunity, transplant rejection, and AIDS.

Some viruses also produce cytokine-binding proteins or cytokine mimics. The evolution of such anti-cytokine strategies by microbial pathogens is good biological evidence of the importance of cytokines in organizing and promoting effective anti-microbial immune responses. The poxviruses, for example, have been shown to encode a soluble TNF-binding protein and a soluble IL-1-binding protein. Since both TNF and IL-1 exhibit a broad spectrum of activities in the inflammatory response, these soluble cytokine-binding proteins may prohibit or diminish the inflammatory effects of the cytokines, thereby conferring upon the virus a selective advantage. Epstein-Barr virus produces an IL-10-like molecule (viral IL-10 or vIL-10) that binds to the IL-10 receptor and, like cellular IL-10, suppresses TH1-type cell-mediated responses (see the next section), which are effective against many intracellular parasites such as viruses. Molecules produced by viruses that mimic cytokines allow the virus to manipulate the immune response in ways that aid the survival of the pathogen. This is an interesting and powerful modification some viruses have undergone in their continuing struggle to overcome the formidable barrier of host immunity. Table 12-3 lists a number of viral products that mimic cytokines or their receptors.

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