Review
Signaling by Type I and II cytokine receptors: ten years after

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Abstract

Discovered during the past ten years, Janus kinases and signal transducers and activators of transcription have emerged as critical elements in cytokine signaling and immunoregulation. Recently, knockout mice for all the members of these families have been generated, with remarkably specific outcomes. Equally exciting is the discovery of a new class of inhibitors, the suppressor of cytokine signaling family. The phenotypes of mice deficient in these molecules are also striking, underscoring the importance of negative regulation in cytokine signaling.

Introduction

Cytokines that bind Type I and Type II receptor families are a diverse group of secreted factors involved in embryogenesis, growth, adiposity, fertility, lactation, hematopoiesis, immunoregulation and host defense. The understanding of the positive and negative signaling elements used by these two families has exploded over the past ten years. Consequently, a number of comprehensive reviews have been written on this subject 1., 2., 3., 4., 5., 6.; the present review will emphasize recent immunologically relevant findings.

Section snippets

Ligands and receptors: good at sharing

Type I receptors bind factors designated variously as hormones, interleukins, or colony-stimulating factors (Table 1) but, despite the different designations, the ligands all have a common four-α-helical structure [7]. The receptors are transmembrane proteins with conserved Cys residues and a WSXWS motif extracellularly. Intracellularly, the receptors are more divergent but have a conserved membrane-proximal domain including a hydrophobic α-helical segment that serves to bind Janus kinases

Jaks

Jaks constitutively bind the membrane-proximal domains of Type I and II cytokine receptors and appear to be the major initiators of signaling induced by cytokines that use these receptors (Table 1). Four mammalian Jaks have been identified—Jak1, Jak2, Jak3 and Tyk2—and they are a small but evolutionarily conserved family with orthologues in teleosts, birds and insects.

Stats

After activation, the Jaks phosphorylate receptor subunits on tyrosine residues to recruit proteins with SH2 domains or phosphotyrosine-binding (PTB) domains. These proteins, in turn, are also phosphorylated by Jaks, coupling cytokine stimulation to a number of pathways, including the Ras/Raf/MAPK and phosphatidylinositol 3′ kinase (PI3′-K)/Akt pathways.

Phosphorylation of cytokine receptors also generates docking sites for a class of SH2-domain-containing cytosolic molecules termed signal

Stat structure

Dimeric Stats bind to DNA in a clamp-like structure, similar to NF-κB and p53 but with fewer direct contact sites with the DNA backbone (Fig. 3) 34., 35., 36.. Carboxy-terminal to the central DNA-binding domain (residues ∼300–500) is a linker domain, an SH2 domain (residues ∼575–690) and a conserved site of tyrosine phosphorylation; phosphotyrosine-SH2 interactions form the hinge of the clamp. Thus the SH2 domain is responsible for two key functions of the Stats: firstly, binding phosphorylated

Stat function

The critical functions of Stat1 and Stat2 in transmitting cytokine dependent signals were first established through the use of mutagenized cell lines defective in IFN-mediated responses. Now, mice deficient in each of the Stats have been generated and in some cases mice deficient in multiple Stats have been produced. These mice clearly demonstrate the nonredundant functions of specific Stats.

Mechanisms of attenuating cytokine signaling

Of equal importance to the positive mechanisms initiated by cytokine signals are the negative regulatory mechanisms that serve to dampen or terminate cytokine signals 69., 70.. Accordingly, there are a number of mechanisms presently identified—their importance being vividly demonstrated by mice lacking these inhibitors.

The SOCS family — cytokine-inducible feedback inhibitors

CIS (cytokine-inducible SH2-domain-containing protein), the first member of this family, was identified as an immediate-early gene, induced by IL-3, that inhibited signaling and proliferation [70]. Using different strategies, three groups subsequently separately cloned another family member, termed SOCS1 (suppressor of cytokine signaling 1), JAB (JAK binding protein) and SSI1 (Stat-induced Stat inhibitor 1) 71., 72.. The SOCS/CIS/SSI family now includes eight members, CIS and SOCS1-SOCS7 [73] (

PIAS

PIAS are a family of constitutively expressed negative regulators of Stats and four members have been identified: PIAS-1, -3, -X and -Y. They share homology amongst themselves but have no previously characterized motifs [89]. PIAS proteins may not be specific for Stat interaction, as PIAS1 was previously described as a helicase 11 interacting protein; the in vivo relevance of this family of proteins will need to be assessed by the production of the relevant knockout mice.

Phosphatases in cytokine signaling

Given the importance of tyrosine kinases in initiating signaling, it comes as no surprise that tyrosine phosphatases are also important inhibitors. For instance, SHP-1 is an important negative regulator, as illustrated by the ‘motheaten mice’ phenotype. The lack of SHP-1 affects almost all hematopoietic lineages and results in the characteristic motheaten appearance of the coat and fatal pneumonitis resulting from unchecked neutrophil and macrophage proliferation [90]. Several hematopoietic

Conclusions

Over the past 10 years, there has been enormous progress in determining how cytokine signaling is initiated and how it is attenuated. With the completion of the sequencing of the human genome and the use of bioinformatic tools, we will soon know all of the cyokines and receptors in this family. However, the complexity of shared receptor subunits and alternative receptors will no doubt complicate the analysis of these new members.

Jaks have emerged as a small family of tyrosine kinases with

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •of special interest

  • ••of outstanding interest

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