Cytokine Receptor Superfamily Signaling

A number of cytokines can be functionally grouped by their similarity in structure as well as by the similarity of the receptors that they utilize. One group of 26 cytokines (Table 1) is characterized by a common predicted 4-a-helical bundle structure [1]. This group of cytokines is further characterized by their common utilization of receptors that are members of the cytokine receptor superfamily [2]. The defining structural elements of the receptors include a cytokine binding module that typically contains two fibronectin type III domains with four positionally conserved cysteine residues in the extracellular domain. In the membrane-proximal region of the extracellular domain, most receptors also contain a WSXWS motif of unknown function. The cytoplasmic domains of the cytokine receptors have only very limited similarity, located in the membrane-proximal region and consisting of what has been termed the box 1 and box 2 motifs. Based on structural considerations, the receptors are often further divided into class I and class II receptors, as indicated in Table 1. A single gene (dom) in Drosophila has functional and structural similarity to the mammalian cytokine receptor superfamily, with the greatest similarity being with the IL-6 subfamily of receptors [3]. This would suggest that the cytokine receptor superfamily has recently evolved to provide expanded opportunities for physiological regulation of cell functions in vertebrates.

As shown in Table 1, a functional cytokine receptor can consist of one or more chains. The nature of the contributions of the individual chains can be quite different depending upon the complex. Frequently a receptor chain contributes only to affinity of cytokine binding. For example, the a-chain of the interleukin-2 (IL-2) receptor, which is the only receptor component listed in Table 1 that is not structurally of the cyto-kine receptor superfamily, increases the affinity of the cytokine binding complex approximately 10-fold. Conversely, the a-chain of the IL-6 receptor binds the cytokine either as a component of the cell-surface complex or as a soluble extracellular protein. The complex of IL-6 and the IL-6 receptor a-chain in turn has high-affinity binding for the P component of the complex gp130. Similarly, the receptors for IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 have a low-affinity, ligand-specific binding chain (a) that associates with a signal transducing chain that is shared (Pc) or, in the case of IL-3 in mice, with a highly related but specific signaling chain (PIL3). Finally, a number of receptors have two chains that are required for signal transduction. For example, in the IL-2 subfamily of receptors both the unique P-chain and the yc are required for signal transduction. Similarly, within the type II receptors, the cytoplasmic domains of both chains are required for signal transduction.

In all the receptor complexes, one or more of the receptor chains associates with one or more of the Janus family of protein tyrosine kinases (Jak), as indicated in Table 1 [4-6]. The Jak family of kinases consists of four members (Fig. 1). The family members have a large amino-terminal domain that contains blocks of homology among family members. It is through this region that the Jaks have been shown to interact with receptor chains. The carboxyl domain contains a pseudokinase domain followed by a functional protein tyro-sine kinase catalytic domain. The role of the pseudokinase

Table I

Cytokine receptor

Chains Associated Janus kinases

Type I receptors

Single-chain/Jak2

Erythropoietin (EPO) 1

Thrombopoietin (TPO) 1

Growth hormone (GH) 1

Prolactin (PRL) 1 Common ß chain

Interleukin-3 2 Granulocyte-macrophage CSF 2

Interleukin-5 2

Common y or y-like:

Interleukin-2 3

Interleukin-4 2

Interleukin-7 2

Interleukin-9 2

Interleukin-13 2

Interleukin-15 2

Interleukin-21 2 Thymic stromal lymphopoietin 2 IL-6 family:

Granulocyte-CSF 1

Interleukin-6 2

Leukemia inhibitor factor 2

Ciliary neurotrophic factor 3

Cardiotrophin 1 2

Oncostatin M 2

Interleukin-11 2

Interleukin-12 1

Type II receptors

Interferon-Y 2

Interleukin-10 2

a, ßc (Jak2), or ßIL3 (Jak2) a, ßc (Jak2) a, ßc (Jak2)

Yc (Jak3) a,L4 (Jakl), Yc (Jak3) aIL7 (Jakl), Yc (Jak3) aIL9 (Jakl), Yc (Jak3) a,L4 (Jakl), a,Ll3 (Tyk2)

aLIFR (JaklX ßgpl30 (Jakl)

a (Jakl), ß (Tyk2) a (Jakl), ß (Jak2) a (Jakl), ß (Jak2)

domain is not known, although some studies have shown that it negatively influences kinase activity and may confer specificity. Unfortunately, no molecular structures have been reported for a Jak. The association of Jaks with receptor chains has been shown to be variable and to exist prior to ligand binding or following ligand binding. Whether the variability is due to technical differences in detecting the association prior to ligand binding or an inherent difference in the nonligated complex is not known.

Irrespective of the number of receptor chains and their individual contributions, the primary function of the complex is to induce the aggregation of the signal transducing component of the complex to activate the associated Jaks.

Figure 1 Structure and properties of the Janus family of protein tyrosine kinases.

Through the use of cross-linking approaches, ligand induces the aggregation of a number of receptor complexes, resulting in the formation of very large complexes. Recent studies have identified small molecules that can also induce receptor aggregation and thereby mimic ligand binding [7,8]. In one case, it was shown that drug binding occurred at sites distinct from the ligand binding region. Regardless, like ligand binding, drug binding results in the activation of receptor-associated Jaks.

The activation of Jaks involves the transphosphorylation of a specific tyrosine in the activation loop that dramatically increases kinase activity. In addition, there are multiple additional sites of auto- or transphosphorylation, but the potential significance of these additional phosphorylation sites has not been examined in detail. From the structure of the known receptor complexes, it can be deduced that Jak2 is capable of activation in complexes in which Jak2 is the only family member present. However, in the other complexes, it has not been determined whether more than one Jak is required for transphosphorylation between different Jaks. For example, it is known from the phenotypes of Jak-deficient mice that both Jakl and Jak3 are required for the function of the IL-2 subfamily of cytokines receptors. In addition, evidence has been presented that the Jaks may be required in the receptor complex to form a high-affinity receptor complex [9].

The essential role that the Jaks play in cytokine receptor signaling has been established through the derivation of mice deficient in one or more of the Jaks [4]. For example, a deficiency in Jak3 results in a phenotype of severe combined immunodeficiency (SCID) due to the lack of function of the IL-2 subfamily of cytokine receptors. Genetic deficiencies of Jak3 also occur in children, for whom the deficiency is similar to that associated with a SCID phenotype. Jak2 deficiency is linked with an embryonic lethality caused by the lack of production of sufficient red cells, and Jakl deficiency is associated with a perinatal lethality and with loss of function of the IL-6 and IL-2 subfamilies of receptors. Finally, Tyk2 deficiency specifically affects the interferon (IFN)-a/p receptor and IL-12. Importantly, in addition to confirming the role of these kinases in cytokine receptor superfamily signaling, analysis of Jak-deficient mice failed to identify an essential role for the kinases in other receptor complexes, in spite of the observation that Jaks have frequently been shown to be inducibly tyrosine phosphorylated in other receptor systems. In Drosophila, a single Jak (hopscotch, hop) is critical for signal transduction through the single Drosophila cytokine receptor gene (Dome, dome) [3]. The identical nature of the phenotypes of mutations of hop and dome suggest that, as in mammals, the receptor/Jak complex is a dedicated signaling complex.

The cytokine receptor superfamily members activate a variety of signal transduction pathways. One of the most consistently activated pathways is that of induced tyrosine phosphorylation of the transcription factors of the signal transducers and activators of transcription (STATs) family. The details of this family of transcriptions factors are covered elsewhere in this Handbook; however, in general terms, the STATs mediate the specific physiological functions associated with individual cytokines [10]. For example, the function of IFNs to elicit an antiviral response is dependent on STAT1 and, conversely, the primary function of STAT1 is to mediate these responses. Equally striking, STAT4 and STAT6 mediate the unique physiological responses induced by IL-12 or IL-4, respectively. This specificity is dramatically illustrated by the observation that Epo, Tpo, GH, and PRL all induce the activation of STAT5; the physiological functions of GH and PRL are totally dependent upon this activation, but the functions of Epo and Tpo are not.

In addition to specific physiological functions, however, many cytokines have as their primary function the ability to promote the proliferation and survival of cells. The elements that are involved in this response are largely unknown. For example, the primary function of Epo is to expand early ery-throid lineage cells to provide sufficient numbers to sustain embryonic development. This capability is not unique to Epo, as the prolactin receptor can mediate the same expansion [11]. Conversely, the cytoplasmic domain of the Epo receptor can fully support the expansion and differentiation of granulocytes when it replaces the cytoplasmic domain of the G-CSF receptor in vivo [12]. The ability of the cytoplas-mic domain of the Epo receptor to function requires only a small portion of the cytoplasmic domain and specifically does not require receptor tyrosines or the ability to activate a STAT-dependent pathway [13]. The conclusion from these types of studies is that, in these cases, the primary function of the receptor complex may be to activate the Jaks, which then function in much the same manner as the receptor tyrosine kinases by recruiting critical signaling mediators to the kinase.

References

1. Callard, R. and Gearing, A. (1994). The Cytokine Facts Book. Academic Press, San Diego.

2. Nicola, N. A. (1994). Guidebook to Cytokines and Their Receptors. Oxford University Press, Oxford.

3. Brown, S., Hu, N., and Hombria, J. C.-G. (2001). Identification of the first invertebrate interleukin Jak/STAT receptor, the Drosophila gene domeless. Curr. Biol. 11, 1700-1705.

4. O'Shea, J. J., Gadina, M., and Schreiber, R. D. (2002). Cytokine signaling in 2002: new surprises in the Jak/STAT pathway. Cell 109(suppl.), S121-S131.

5. Gadina, M., Hilton, D., Johnston, J. A., Morinobu, A., Lighvani, A., Zhou, Y. J., Visconti, R., and O'Shea, J. J. (2001). Signaling by type I and II cytokine receptors: ten years after. Curr. Opin. Immunol. 13, 363-373.

6. Rane, S. G. and Reddy, E. P. (2000). Janus kinases: components of multiple signaling pathways. Oncogene 19, 5662-5679.

7. Tian, S. S., Lamb, P., King, A. G., Miller, S. G., Kessler, L., Luengo, J. I., Averill, L., Johnson, R. K., Gleason, J. G., Pelus, L. M., Dillon, S. B., and Rosen, J. (1998). A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor. Science 281, 257-259.

8. Duffy, K. J., Darcy, M. G., Delorme, E., Dillon, S. B., Eppley, D. F., Erickson-Miller, C., Giampa, L., Hopson, C. B., Huang,Y., Keenan, R. M., Lamb, P., Leong, L., Liu, N., Miller, S. G., Price, A. T., Rosen, J., Shah, R., Shaw,T. N., Smith, H., Stark, K. C., Tian, S. S., Tyree, C., Wiggall, K. J., Zhang, L., and Luengo, J. I. (2001). Hydrazinonaphtha-lene and azonaphthalene thrombopoietin mimics are nonpeptidyl promoters of megakaryocytopoiesis. J. Med. Chem. 44, 3730-3745.

9. Gauzzi, M. C., Barbieri, G., Richter, M. F., Uze, G., Ling, L., Fellous, M., and Pellegrini, S. (1997). The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor. Proc. Natl. Acad. Sci. USA 94, 11839-11844.

10. Ihle, J. N. (2001). The STAT family in cytokine signaling. Curr. Opin. Cell Biol. 13, 211-217.

11. Socolovsky, M., Dusanter-Fourt, I., and Lodish, H. F. (1997). The pro-lactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors. J. Biol. Chem. 272, 14009-14012.

12. Semerad, C. L., Poursine-Laurent, J., Liu, F., and Link, D. C. (1999). A role for G-CSF receptor signaling in the regulation of hematopoietic cell function but not lineage commitment or differentiation. Immunity 11, 153-161.

13. Zang, H., Sato, K., Nakajima, H., McKay, C., Ney, P. A., and Ihle, J. N. (2001). The distal region and receptor tyrosines of the Epo receptor are non-essential for in vivo erythropoiesis. EMBO J. 20, 3156-3166.

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