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Originally published online as doi:10.1189/jlb.1003507 on December 23, 2003

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(Journal of Leukocyte Biology. 2004;75:743-748.)
© 2004 by Society for Leukocyte Biology

Are SOCS suppressors, regulators, and degraders?

James A. Johnston1

Department of Microbiology and Immunology, Queen’s University, Belfast, Northern Ireland

1 Correspondence: Department of Microbiology and Immunology, Queen’s University, Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland. E-mail: jim.johnston{at}qub.ac.uk


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ABSTRACT
 
Suppressors of cytokine signaling have been identified as inhibitors of cytokine signaling and have been shown to act in a classical feedback loop. The prototype members of this family, cytokine-inducible Src homology 2-containing protein and suppressors of cytokine signaling SOC was cloned as cytokine-inducible immediate early gene that could inhibit the activation of signal transducer and activator of transcription factors and block biological responses to several cytokines. Although steady progress has been made in the identification of SOCS and their physiological importance, precisely how SOCS proteins function has not yet been discovered. Many recent findings indicate that the SOCS act as adaptors that regulate the turnover of certain substrates by interacting with and activating an E3 ubiquitin ligase. Here, I explore recent evidence (presented at the International Cytokine Society meeting in Dublin, Ireland, September 2003) that SOCS molecules may not act simply as regulators of cytokine responses but may also play an essential role in determining cell fate and controlling cell differentiation.

Key Words: JAKs • STAT5 • cytokine signaling • Janus kinase


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INTRODUCTION
 
Cytokines bind to multisubunit receptor complexes and activate Janus kinases (Jaks), which in turn phosphorylate many downstream pathways including signal transducers and activators of transcription (STATs), mitogen-activated protein kinases, and phosphoinositol 3-kinase. The strength and duration of the response are regulated, at least in part by the family of proteins referred to as suppressors of cytokine signaling (SOCS). There are eight SOCS family members including cytokine-inducible Src homology (SH) 2-containing protein (CIS) and SOCS1–7 [1 2 3 4 5 ]. Expression of CIS and SOCS1–3 is exquisitely regulated when cells are activated by cytokines such as interleukin (IL)-2 and interferon-{gamma} (IFN-{gamma}). The model predicts that upon cytokine binding, SOCS genes are rapidly up-regulated, and their protein products block further signaling by inactivating the JAK–STAT pathway, thus blunting cytokine responses (Fig. 1 ).



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  		Figure 1. SOCS inhibit cytokine signal transduction. Cytokines induce dimerization of receptors leading to the activation of JAKs that tyrosine-phosphorylate the cytoplasmic region of the receptor, creating docking sites for interacting proteins such as STATs. Following phosphorylation by JAKs, the STATs are activated and translocate to the nucleus, where they bind DNA and induce target-gene transcription. SOCS1–3 and CIS are rapidly induced genes and act in a feedback loop to inhibit signal transduction.

These SOCS family proteins contain a central SH2 domain and a conserved C-terminal SOCS box thought to interact with an E3-ligase complex [6 ]. To date, a number of mechanisms have been suggested through which the SH2 domain can bind to phosphotyrosines on signaling intermediates, particularly receptor chains and JAKs, leading to the inhibition of signal transduction or as in the case of CIS, blocking STAT recruitment to the receptors.

CIS was initially discovered to bind directly to phosphorylated tyrosine residues of the erythropoietin (EPO) receptor and block STAT5 phosphorylation [1 ] and has been shown to inhibit EPO signaling by binding to the receptor at Y401, one of the two STAT5-binding sites [7 ]. Erythroid progenitor cells overexpressing CIS show an increased tendency to undergo apoptosis, suggesting that CIS may keep erythroid development in check [8 ].

SOCS1 function was clearly defined by experiments, demonstrating that it binds to phosphorylated Y1007 within the JAK2 activation loop thereby regulating JAK activity [9 ]. Indeed, the SOCS1–SH2 domain is sufficient for JAK2 binding; however, the SH2 domain and the kinase inhibitory region (KIR) are absolutely required for high-affinity binding and inhibition of JAK2 activity [10 ]. It has also been hypothesized that JAK activity is inhibited by KIR binding to the JAK2 catalytic groove and acting as a pseudosubstrate to prevent substrate access to the JAK catalytic groove (Fig. 1) .

SOCS3 is thought to inhibit cytokine signaling by a mechanism similar to SOCS1. In the presence of the receptor, SOCS3 has a significantly greater ability to interact with JAKs and to inhibit kinase activity in the growth hormone (GH)- and IL-2-induced signaling pathways [11 , 12 ]. The binding affinity of SOCS3 for phosphopeptides derived from the JAKs, the STATs, or the gp130 subunit of the leukemia inhibitory factor (LIF)/IL-6 receptors showed that SOCS3 had by far the highest affinity for gp130 [13 ]. Moreover, the inhibition of gp130 signaling by SOCS3 but not SOCS1 was significantly reduced when the critical phosphotyrosine (Y757) was mutated. This suggests that optimal inhibition by SOCS3 occurs when it is bound to gp130.

The mechanisms of action of the other four SOCS proteins, SOCS4–7, have not yet been established. The SH2 domains of SOCS6 and SOCS7 share 56% amino acid identity and 53% in their SOCS box, making them much more similar to each other than to other SOCS family members. SOCS4–7 contain relatively large amino-termini of more than 350 amino acids with no identifiable protein-interaction motifs. Unlike other SOCS family members, SOCS6 does not interact with JAK2 or inhibit signaling by GH, LIF, or prolactin (PRL). However, SOCS6 binds to the insulin receptor in response to insulin treatment and inhibits downstream signaling events such as the activation of extracellular-regulated kinase (ERK)1/2, Akt, and insulin receptor substrate-1 (IRS-1) [14 ]. SOCS7 (also called neutrophil-activating polypeptide-4) was shown to interact with Nck, Ash, phospholipase C{gamma}, and the epidermal growth factor receptor. The significance of these interactions is not yet clear, but they undoubtedly have important roles in signal transduction.


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SOCS CAN BIND TO E3 LIGASES
 
The data accumulated so far would suggest that proteins that bind SOCS are targeted for proteasomal degradation. This is thought to result from the function of the SOCS box itself. Database analysis has shown that a large number of proteins contain this domain. Many of these proteins, rather than containing a SH2 domain, contain other domains thought to be involved in protein–protein interactions. These include proteins containing ankyrin repeats (ASB), SPRY domains (SSB), or WD40 repeats (WSB) [5 ]. Clues to the function of the SOCS box became evident when it was realized that the SOCS box was conserved in other previously characterized proteins including the Von-Hippel-Lindau (VHL) tumor suppressor gene, MUF-1, and Elongin-A. Kamura et al. [15 ] purified the novel, leucine-rich repeat containing the BC-box containing protein MUF1 from rat liver and showed that it could assemble with a Cul5/Rbx1 complex to reconstitute ubiquitin-ligase activity. Additionally, they showed that the BC-box proteins Elongin-A, SOCS1, and WSB1 could also form ubiquitin ligases by complexing with Cul5/Rbx1. The VHL protein and Elongin-A are known to interact with Elongin-C and via this interaction, Elongin-B and an E3-ligase complex [6 ]. In the presence of Elongin-C, VHL interacts with Elongin-B, the Cullin family member Cul2, and the ring finger protein Rbx1, thereby activating ubiquitin E3-ligase activity (Fig. 2 ). The model predicts that the SOCS box can act like the BC box of the VHL complex by acting as an adaptor between an E3 ligase and a specific substrate. Individuals inheriting mutations in VHL tumor suppressor gene are predisposed to renal tumors, retinomas, and tumors of the central nervous system—most likely because of enhanced transcription of growth factor genes. The VHL protein can down-regulate the hypoxia-induced transcription factor (HIF)1{alpha}, and thus, HIF1{alpha} accumulates in cells deficient in VHL protein.



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  		Figure 2. Structure of the SOCS–Elongin-E3 ubiquitin-ligase interaction. SOCS and VHL interact with specific substrates such as JAK and HIF1{alpha}. The SOCS box region binds to Elongin-C and Elongin-B, which in turn bind the SCF (Skp1, Cde53, and F-box protein) like complex containing Skp-1 and the Cullin family member, Cul-5, and a ring finger-containing protein Rbx1 (Roc1). This acts as an E3 ubiquitin ligase, which ligates ubiquitin unto the target substrate. In the case of SOCS, JAKs have been suggested as possible substrates.

SOCS1 has been suggested to act as a ubiquitin ligase that regulates the half-life of Vav [16 ], the oncogene Tel–JAK2, and JAK kinases, as well as IRS-1/2 [17 , 18 ]. Some recent reports suggest that Elongin-C links SOCS proteins and E3-ligase activity, thus targeting their degradation by the proteasome. In agreement with this, mutations or post-translational modifications of SOCS1 that disrupt Elongin-C interaction stabilize the protein [19 , 20 ]. However, in contrast to these reports, others have suggested that Elongin-C can stabilize SOCS protein expression, and disruption of this interaction leads to proteasome-mediated SOCS destruction [21 ]. The Elongin-C-binding partner, the VHL tumor suppressor protein, regulates the stability of HIF1, and mutations in the VHL SOCS box that interfere with its Elongin-C interaction destabilize the protein, resulting in a marked reduction in protein levels. This is thought to be responsible for the loss of function phenotype in VHL syndrome [22 ]. Therefore, by extension, the binding of Elongin-C to SOCS proteins most likely enhances its stability.


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PHOSPHORYLATION REGULATES SOCS PROTEIN TURNOVER
 
Phosphorylation has been shown to activate proteasome-mediated degradation. Tyrosine residues on kinases such as ZAP-70 recruit the ring finger protein c-Cbl through its phosphotyrosine-binding domain. c-Cbl bridges the kinases to an E2 ubiquitin ligase and facilitates protein turnover and down-regulation of signal transduction [23 ]. Degradation of p27 by a similar Skp1–Cullin mechanism is also controlled by phosphorylation. The degradation of p27 requires its phosphorylation and is mediated by an F-box protein that associates with Skp1, Cul1, and Rbx1 to form the SCF (Skp2) ubiquitin-ligase complex (Fig. 2) [24 ]. We have now found that tyrosine phosphorylation decreases SOCS3 protein half-life by disrupting the interaction between SOCS3 and Elongin-C [25 ]. Sequence comparison reveals a high degree of conservation of SOCS-box tyrosine residues. The tyrosines phosphorylated in SOCS3 are conserved in 70% of all SOCS family members and also in SOCS proteins WSB-2, ASB-1, and ASB-2 [25 ], suggesting that tyrosine phosphorylation may also regulate the stability of these proteins. It will be important to determine whether other SOCS proteins can also be degraded as a result of phosphorylation.

In this regard, Pim kinase can associate with and phosphorylate the SOCS1 N terminus, resulting in stabilization of the protein [20 ]. Accordingly, SOCS1 protein levels are significantly reduced in the Pim-1–/–, Pim-2–/– mice, suggesting that the Pim kinases may regulate cytokine-induced JAK–STAT signaling through modulation of SOCS1 protein levels. The Pim kinases and SOCS1 are induced by a variety of cytokines, and the interaction between Pim and SOCS1 may represent a mechanism by which cytokines cross-regulate one another.

These data are consistent with a model in which the Elongin BC complex protects SOCS proteins from proteasome-mediated degradation while also acting as a molecular bridge between SOCS molecules and the proteasome. Bringing tightly regulated ubiquitination machinery into direct contact with SOCS would facilitate rapid SOCS turnover in response to an appropriate stimulus that releases Elongin-C from the SOCS box. In support of this model, a naturally occurring isoform of SOCS3, generated by alternative translation initiation, has been identified that appears to encode a truncated SOCS3 protein, which is more stable than the full-length protein [26 ]. Analysis of its biological activity demonstrated an enhanced ability to inhibit cytokine signaling, presumably through increased stability. The truncated SOCS3 isoform lacks the first 12 N-terminal amino acids including a lysine residue at position 6, which has been shown to be the main site for ubiquitination on SOCS3, further underlining the potential importance of E3 ligase-mediated regulation of SOCS3.


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OTHER MECHANISMS CONTROLLING SOCS PROTEIN HALF-LIFE
 
SOCS1 has also been shown to associate with the tripartite motif (TRIM)8/glioblastoma-expressed RING-finger protein [27 ]. TRIM8 appears to target SOCS1 protein for degradation, indicating that like VHL, SOCS1 turnover may require the recruitment of a ring finger protein such as TRIM8 to activate the degradation process. Whether Elongin-C can protect SOCS1 from degradation in a manner similar to VHL is unknown, as the function of the SOCS–Elongin-C interaction is not clearly understood.

To complicate the story further, although SOCS1 and SOCS3 inhibit signaling by binding activated JAKs and their cognate receptors, SOCS2 has not been shown to have this effect. In fact, it has been shown to markedly enhance STAT activation in response to a variety of stimuli, including GH. Favre et al. [28 ] have demonstrated that at low levels, SOCS2 inhibited GH-induced STAT5-dependent transcription, but at higher levels, it actually restored GH signaling and in fact, blocked the inhibitory effect of SOCS1. SOCS2 is expressed in T cells and is induced by IL-4, -5, and -10 and GH. We have found that IL-2 can induce SOCS2 and SOCS3 but with different kinetics, with SOCS3 being induced much earlier than SOCS2. Unlike other SOCS family members, SOCS2 expression enhanced STAT and ERK phosphorylation following cytokine treatment (J. A. Johnston, unpublished observation). Expression of SOCS2 resulted in a marked proteasome-dependent reduction of SOCS3 protein expression, although SOCS3 mRNA expression was enhanced. Therefore, it appears that SOCS2 enhances signaling responses by accelerating proteasome-dependent turnover of SOCS3. Perhaps competition between various SOCS box-containing proteins accelerates protein turnover, hence regulating expression of other SOCS proteins. Pezet et al. [29 ] have made similar observations in a study of PRL signaling. They demonstrated that SOCS2 associated directly with the prolactin (PRL) receptor and that it suppressed the inhibitory effects of SOCS1 in response to PRL by restoring JAK2 kinase activity. These results could indicate that SOCS2, which is induced later than SOCS1 and SOCS3 in response to cytokines, may act to restore cellular sensitivity by suppressing the inhibitory effect of SOCS1. Given the gigantic phenotype of SOCS2–/– mice, the physiological relevance of this remains to be determined.


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PHYSIOLOGICAL IMPORTANCE OF SOCS1
 
Analysis of knockout mice has established that SOCS1 is absolutely necessary in vivo. Mice lacking SOCS1 die within 3 weeks of birth as a result of fatty degeneration of the liver and hematopoietic infiltrates of many organs, including the pancreas, heart, and lungs [30 ]. This was shown to primarily result from IFN-{gamma} functions, as crossing SOCS1–/– and IFN-{gamma}–/– mice allowed the animals to survive for much longer periods—up until 8 or 9 months without significant pathology. The essential role for the lymphoid population is perhaps not surprising, given that leucocytes are the most important source of IFN-{gamma}. Although mice lacking SOCS1 and IFN-{gamma} are initially healthy, they eventually exhibit a range of inflammatory diseases. However, recently, it has become clear that SOCS1 plays a role in maintaining dendritic cell homeostasis. Hanada et al. [31 ] have reported that SOCS1–/– dendritic cells become hyperactivated in response to cytokines. Using mice where SOCS1 was reintroduced into a SOCS1–/– background under the control of the lck-proximal promoter and the µ enhancer, they showed that the phenotype of these mice was much improved from the SOCS1 knockouts. However, after an extended period, the animals succumbed to infection and on closer analysis, there was a dramatic increase in the activation of dendritic cells. Dendritic cell numbers were increased in the thymus and in the spleen, and the animals exhibited splenomegaly. It is interesting that these animals presented with hypergammaglobulinaemia and skin ulcers early in life and also had other facets of autoimmunity. The levels of B lymphocyte stimulator (BlyS) and the proliferation-inducing ligand (APRIL) accumulated in these dendritic cells, perhaps resulting in the expansion of B cells and autoreactive antibody production. The results indicated that SOCS1 is likely to play an important role in regulating dendritic cell function and in suppression of systemic autoimmunity, suggesting that it is not just important in lymphocytes [31 ].


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SOCS1 INVOLVEMENT IN INNATE IMMUNITY
 
As stated in the introduction, SOCS are not highly expressed in unstimulated cells but are rapidly induced following exposure to cytokines. To date, SOCS are known to be induced by {alpha}-helical cytokines such as IL-6, IL-2, and granulocyte-colony stimulating factor (G-CSF). However, we are now aware that SOCS1 and SOCS3 are not only regulated by cytokines but are also regulated by Toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS) and CpG DNA, and also by inflammatory cytokines such as tumor necrosis factor and IL-1 [32 , 33 ]. Recently, reports have suggested that SOCS1 can strongly inhibit LPS responsiveness and that cells from SOCS1 transgenic animals fail to respond to LPS, suggesting that SOCS1 may have a direct effect on TLR signaling [34 ]. To date, however, the mechanism involved is elusive, particularly as TLR-triggered responses are considered independent of tyrosine phosphorylation, raising the possibility that the mechanism may be indirect.

In further studies, there have been suggestions that SOCS expression can be regulated by chemoattractants, particularly formyl-Met-Leu-Phe (fMLP) and IL-8 (J. A. Johnston, unpublished observations). However, unlike other stimuli, these chemotactic factors appear only to regulate SOCS1, which when induced in response to chemokines in polymorphonuclear neutrophil, temporarily induces potent inhibition of G-CSF signaling (Fig. 3 ). This effect suggests that fMLP and IL-8 play an important role in regulating cytokine and growth factor signals in neutrophils, most likely by inhibiting further cytokine-signaling responses in these cells. Recent evidence suggests that upon G-CSF treatment, SOCS1 and SOCS3 are expressed in primary human neutrophils, thereby negatively regulating G-CSF receptor-mediated signaling [35 ]. The fact that SOCS1 is induced by chemotactic factors provides evidence for SOCS-mediated cross-talk between chemoattractants and cytokine-signaling pathways. G-CSF controls the function of mature neutrophils but is not required during an acute inflammatory response to bacterial products or responses mediated by IL-8 such as chemotaxis and phagocytosis. Therefore, it might be appropriate for the chemokine-stimulated neutrophil to desensitize to many other stimuli. The result would be marked inhibition of other signals once the neutrophils have made the decision to migrate along the chemotactic gradient to the site of infection.



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  		Figure 3. Cross-talk between chemokine and cytokine signal-transduction mechanisms. As shown in Figure 1 , cytokines induce inhibition of their own signaling through the induction of SOCS. Chemokine receptors also induce expression of SOCS1 and consequently, potently inhibit G-CSF signaling in neutrophils. This pathway provides rapid, potent cross-talk between distinct signaling pathways.


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SOCS3 MAKES IL-6 INFLAMMATORY
 
Mice lacking SOCS3 die mid-gestation as a result of placental insufficiency [36 ]. Although the specific role of SOCS3 in placental development is not entirely clear, the findings would suggest that this may be a result of nonredundant importance in LIF-mediated signaling. More recently, three groups have proven that SOCS3 has a nonredundant role in the regulation of gp130 signaling. These findings indicate that the loss of SOCS3 can alter gp130 signaling by prolonging STAT activation, an effect that changes the functional outcome of IL-6 signaling [37 38 39 ]. In fact, in the absence of SOCS3, IL-6 behaves more like the immunosuppressive cytokine IL-10. IL-6 and IL-10 depend on STATs, particularly STAT3, for signaling. Therefore, despite the rapid induction of SOCS1 and SOCS3 by IFN-{gamma} and IL-6, there appears to be little functional redundancy. STAT3 activation in response to IL-10 was not enhanced in SOCS3 null macrophages, suggesting that at least in the myeloid lineage, SOCS3 specifically targets gp130 family cytokines.


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SOCS3 AND THE T HELPER CELL TYPE 2 (Th2) RESPONSE
 
Although SOCS clearly plays a role in controlling the immediate response to cytokines, there is mounting evidence that SOCS expression is also highly regulated during Th cell differentiation and may strongly influence the disease process. SOCS3 is expressed during Th2 differentiation and is switched off in Th1 cells [40 ]. Conversely, SOCS5 is expressed in Th1 cells but is not expressed in Th2 cells. Seki et al. [41 ] demonstrated that SOCS5 was preferentially expressed in committed Th1 cells and interacted with the cytoplasmic region of the IL-4R{alpha}. This suggests an important role for SOCS5 in regulating Th1 and Th2 balance. Conversely, committed Th2 cells express SOCS3, whereas committed Th1 cells have completely shut down SOCS3 expression [42 ]. This paper correlated SOCS3 expression with severity in atopic dermatitis and asthma, raising the possibility that high SOCS3 expression in peripheral blood T cells may be attributable to the accumulation of Th2 cells, thus leading to increased risk of Th2-mediated type 1 hypersensitivity. The finding that SOCS3 exhibits an expression profile, which correlates with serum immunoglobulin E levels and with the Th2 marker CCR4, further supports this idea [42 ]. One could argue that SOCS3 expression may be a response to cytokines secreted from activated T cells at the inflammatory site and may be a secondary, noncausative event. However, the fact that other SOCS are not regulated in this way in Th2 cells and that high levels of SOCS3 expression (but not other SOCS family members) were observed in allergic patients points to a likely importance in Th2-mediated immunity.

The observations suggest that SOCS3 can influence Th2 development and that increased Th2 responses most likely result from functional inhibition of IL-12-mediated signaling during Th cell differentiation. This idea is supported by the reduction of IL-12-induced T-bet and IL-12Rß2 expression in T cells overexpressing SOCS3 and the observed reduction of IL-12-induced Th1 differentiation [42 ]. However, these findings contrast sharply with the theory that SOCS molecules act as autocrine negative-feedback regulators. Indeed, the data suggest that in atopic patients, SOCS3 biases Th cell differentiation toward Th2, and therefore, SOCS3 could prove a useful, therapeutic target.


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CONCLUSIONS
 
It is clear that some SOCS family members can potently inhibit cytokine signal transduction, but the functions of other family members may not be simply inhibitory. In fact, SOCS are unquestionably involved in other functions including terminal differentiation of T cells, cross-talk between signaling pathways, regulation of pro- and anti-inflammatory signals, and targeting signaling intermediates for degradation. The degradation appears to be mediated by the SOCS box that can recruit an E3 ligase, but the targets and its importance in inflammation and oncogenesis are unclear. Given the remarkable number of proteins that contain a SOCS box, understanding the mechanisms by which this degradative process is regulated will most likely prove highly important in understanding disease.


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ACKNOWLEDGEMENTS
 
The Wellcome Trust (Grants 070304/2/03/2 and BBSRC 81/C17863) supported J. A. J. The author thanks Drs. Massimo Gadina and Joanne Elliott for critically reviewing the manuscript.

Received October 28, 2003; accepted October 29, 2003.


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