Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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(Journal of Leukocyte Biology. 2001;70:348-356.)
© 2001 by Society for Leukocyte Biology

Negative regulation of cytokine signaling

Christopher J. Greenhalgh and Douglas J. Hilton

The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria, Australia

Correspondence: Dr. Christopher J. Greenhalgh, The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: greenhalgh{at}wehi.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PHOSPHATASES
 SOCS
 CONCLUDING REMARKS
 REFERENCES
 
Cytokines use complex signaling cascades to elicit their biological effects, many of which involve phosphorylation as a mechanism of activation. Rapid and efficient attenuation of cytokine signals is crucial to maintaining regulation of these processes and to preventing toxic side effects. Phosphatases have been shown to be involved in these regulatory processes, but more recent research has seen the discovery of two new families of negative regulators, the suppressor of cytokine signaling (SOCS) and protein inhibitors of signal transducer and activator of transcription (STAT) (PIAS) protein families. SOCS proteins are induced by and inhibit many cytokine-signaling systems in a classic negative-feedback loop, and the generation of transgenic and knockout models has greatly increased our understanding of their physiological functions. PIAS proteins interact with the transcriptional mediators of cytokine action, the STATs, to suppress their DNA-binding activity. These three classes of molecules form what is now emerging as an integrated system for deactivating cytokine signaling at a number of levels, from the receptor to the transcription factor.

Key Words: SOCS • Janus kinase • STAT • PIAS • phosphatase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PHOSPHATASES
 SOCS
 CONCLUDING REMARKS
 REFERENCES
 
Cytokines and growth factors exert their biological effects by binding to specific cell surface receptors on target cells. Although the numbers and roles of cytokines are diverse, some common themes about their mechanisms of action can be deduced. After binding to their receptors, many cytokines induce receptor dimerization and recruitment of members of the Janus kinase (JAK) family, which in turn cross-phosphorylate both each other and the cytoplasmic domains of the receptors on tyrosine residues. This provides docking sites for latent transcription factors called signal transducers and activators of transcription (STATs). These transcription factors become phosphorylated after docking and then dimerize before entering the nucleus and initiating transcription of target genes [for a full review of JAK/STAT signaling, see reference 1]. The activation of such potent signaling cascades also requires specific, fine-tuned mechanisms to negatively regulate them. Although understanding of the proteins that mediate cytokine signal transduction has increased substantially, analysis of the mechanisms by which signaling is tempered has lagged behind.

Much of our understanding of how negative regulation of cytokine signaling is accomplished has focussed on the actions of phosphatases, but more recent research has demonstrated the contributions of newly identified families of inhibitory molecules to this attenuation. This review briefly summarizes what is known about phosphatase regulation of cytokine signaling and then highlights and analyzes two new negative-regulator families, the protein inhibitors of STATs (PIAS) and the suppressor of cytokine signaling (SOCS) proteins.


   PHOSPHATASES
TOP
 ABSTRACT
 INTRODUCTION
 PHOSPHATASES
SOCS
 CONCLUDING REMARKS
 REFERENCES
 
SHP-1
Tyrosine phosphorylation is a rapid and reversible process that many cell-signaling systems use to signify activation. The most obvious candidates for the regulation of phosphorylation are phosphatases. One of the most detailed studies of a phosphatase involves the mutant motheaten mouse strain, which harbors a mutation in an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase called SHP-1. Motheaten mice suffer from loss of hair, major lymphoid and myeloid abnormalities, immunodeficiency, and autoimmune diseases [2 3 4 5 ]. Cloning has revealed that SHP-1 is composed of two SH2 domains preceding a phosphatase domain and is predominantly expressed in hematopoietic cells. Although SHP-1 is known to be a regulator of B and T cell receptor signaling [for a complete review of these functions, see ref 6 ], it has also been shown to suppress a variety of cytokine signaling systems. Bone marrow progenitors from motheaten mice have been shown to have enhanced proliferative responses to granulocyte-macrophage colony-stimulating factor (GM-CSF) and CSF-1 [7 , 8 ], whereas SHP-1 has been shown to suppress the actions of erythropoietin (EPO) [9 ], IL-3 [10 ], Steel factor [11 ], and interferon (IFN) {gamma} [12 ]. The mechanism by which SHP-1 inhibits these pathways is being elucidated and is thought to involve the deactivation of receptor kinases and JAKs. SHP-1 has been shown to bind to tyrosine-phosphorylated EPO receptor and to dephosphorylate JAK2, whereas there are other examples in which SHP-1 has bound directly to JAK2 via an SH2-independent mechanism [9 ]. SHP-1 is also thought to function by binding directly to cytokine receptors to dephosphorylate signaling components. This is emphasized in a Finnish family that has elevated hematocrit levels because they carry a mutant EPO receptor that is truncated and unable to bind SHP-1 [13 ]. The fact that SHP-1 is constitutively expressed infers that its inhibitory effects are rapidly exerted after cytokine receptor activation. This is in contrast to many SOCS proteins (discussed below), which are expressed only in response to cytokine signaling.

CD45
Although many membrane-bound phosphatases are known to act in hematopoietic-signaling pathways, probably the best studied of these is CD45. CD45 is a transmembrane phosphatase that is highly expressed on all nucleated hematopoietic cells and has been shown to be extensively involved in T and B cell antigen receptor signaling and lineage development, as well as having a role in regulating adhesion and apoptosis [reviewed in ref 14 ]. Only very recently was it discovered that CD45 also has a function in regulating cytokine signaling. Mast cells lacking CD45 were found to proliferate faster in response to interleukin (IL) 3 compared with wild-type cells, implicating CD45 in regulating IL-3 signaling [15 ]. Examination of the IL-3-signaling cascade identified JAK2 as being hyperphosphorylated in the absence of CD45 with enhanced JAK2 kinase activity evident within 2 min of IL-3 stimulation. In vitro studies confirmed that CD45 could directly dephosphorylate JAK2 and identified similar roles for CD45 in negatively regulating IFN-{gamma} and EPO signaling [15 ]. Whether CD45 acts on other cytokine-signaling pathways in a similar manner is unclear at present, but given that it interacts with JAKs, which are used in many hematopoietic signaling cascades, it is conceivable that CD45 plays a greater role than currently understood.


   SOCS
TOP
 ABSTRACT
 INTRODUCTION
 PHOSPHATASES
 SOCS
CONCLUDING REMARKS
 REFERENCES
 
Discovery
SOCS-1 was discovered by three groups using different experimental approaches. The first group used an expression library to identify molecules capable of blocking IL-6-mediated macrophage differentiation of M1 cells [16 ]; the second group used a yeast two-hybrid to detect molecules able to interact with JAK2 [17 ]; and the third group used a screen with antibodies to find proteins with homology with the SH2 domain of STATs [18 ]. These three approaches identified a molecule that contained an SH2 domain and had structural and sequence similarities to an immediate early gene called CIS (cytokine-inducible SH2-containing protein) [19 ]. Initial overexpression studies indicated that this molecule could inhibit a number of cytokine-signaling pathways and was subsequently called SOCS-1, but it is also known as STAT-induced STAT inhibitor (SSI-1) or JAK (JAB) 2-binding protein. Database searches reveal that SOCS-1 is part of a family that now includes eight proteins (SOCS-1–7 and CIS), all of which are characterized by a central SH2 domain flanked by an N-terminal domain of variable length and sequence, and a C-terminal region containing a conserved motif called a SOCS box. More extensive database searching has revealed that a number of other proteins contain this C-terminal SOCS box motif and can be grouped based on the motifs contained within their N-terminal domains: WD-40 repeats (WSB-1 and -2), ankyrin repeats (ASB-1–9), SPRY (SSB-1–3), and small GTPase domains [20 ].

Expression
In contrast to the constitutively expressed phosphatases, SOCS proteins are induced by a wide range of cytokines such as leukemia inhibitory factor (LIF), growth hormone (GH), prolactin, many interleukins, and a host of other growth factors. Table 1 summarizes these data and provides source references, emphasizes the considerable scope of SOCS functions generated by in vitro studies, and implicates a number of SOCS proteins as having pleiotropic actions. The SOCS proteins are found in most hematopoietic tissues. Northern blot analysis of SOCS mRNA expression patterns has revealed high levels of CIS in the kidney, fat, muscle, and liver, and expression of SOCS-1 is found predominantly in the thymus [16 , 57 ]. SOCS-2 mRNA is found in the liver, heart, lungs, and spleen whereas SOCS-3 is most prevalent in the lungs, spleen, and fat [16 , 57 ]. In vivo and in vitro cytokine stimulation time-course studies reveal that SOCS mRNA expression profiles are not identical. For example, SOCS-1 and SOCS-3 mRNAs have rapid and transient expression profiles that tend to peak around 1 h but return to baseline by 4 h in response to GH or IL-6, whereas SOCS-2 initially has lower levels of induction compared with the other SOCS proteins but increases steadily over a longer time [16 , 22 ]. CIS has a similar induction profile to SOCS-1, but rather than returning to baseline, its expression can increase again after 4 h [16 , 22 , 57 ]. The reasons for these different expression patterns are unknown but might reflect differences in their mechanisms of action.


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  		Table 1. Induction and Actions of SOCS Proteins

 
Mechanisms of action
Much research effort has been focused on defining the modes of action of individual SOCS molecules. In vitro studies with SOCS-1 have shown that it interacts directly with active JAKs by binding to their activation loop in a phosphorylation-dependent manner. It is hypothesized that SOCS-1 blocks any further catalytic action through the capacity of the N-terminal portion of SOCS-1 to inhibit ATP from binding to its cleft [17 , 18 , 52 ] (Fig. 1 ). SOCS-3 has also been shown to inhibit cytokine signaling but via a different mechanism than that of SOCS-1. SOCS-3 interacts with many activated receptors including the leptin, GH, gp130, and EPO receptors [50 , 58 59 60 ] and has the ability to bind to JAKs without inhibiting JAK activity [52 ]. Consequently, it is possible that SOCS-3 inhibitory actions require the binding of both an activated receptor and associated JAK to maximize inhibition, as has been shown for the suppression of EPO signaling [50 ]. In contrast to the mechanisms of SOCS-1 and -3, CIS was initially discovered for its ability to bind directly to phosphorylated tyrosine residues of the EPO receptor and block STAT5 recruitment and phosphorylation [19 ]. CIS has since been shown to bind to the GH receptor and inhibit STAT5 signaling, and it is hypothesized to be involved in the suppression of STAT5b activity that is observed in female mice [29 , 41 , 61 ]. The targets and mechanisms of SOCS-2 and the other SOCS family members are yet to be established, but the data collected to date affirm that SOCS proteins inhibit cytokine signaling using a number of different mechanisms.



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  		Figure 1. Hypothetical mechanism of SOCS-1-negative regulation of JAKs. On cytokine activation, JAKs are recruited to the receptor complex and become phosphorylated. Phosphorylation alters the activation loop conformation from an inactive structure (A) to an active form (B). This change allows substrates to enter the activation loop region as well as allowing ATP to bind nearby (C). Kinase activity transfers a phosphate group (P) from the ATP to the substrate, yielding ADP and phosphorylated substrate. The subsequent negative-feedback regulation involves the expression of SOCS-1, which binds to the JAK activation cleft preventing further activity by restricting recruitment of ATP and substrate (D). Secondarily to this, components of the proteasome machinery including elongin B (El B), elongin C (El C), and Cullin 2 (Cul2) bind to the SOCS box and ubiquitinate the signaling complex and/or the SOCS proteins (E) to target them for degradation._art>

 
An important component of the negative regulation achieved by SOCS proteins could involve the conserved SOCS box motif located at the C terminus of all SOCS proteins. Interaction studies with many of the SOCS box-containing proteins have found that they bind two molecules called elongin B and elongin C, which are part of the machinery by which proteins are targeted to the proteasome for ubiquitination and degradation [62 , 63 ]. It has been hypothesized that this interaction might function as a mechanism by which cells remove excess SOCS protein when not required [64 ] or, alternatively, dispose of the SOCS-bound signaling complex [63 ]. Thus, SOCS protein-negative regulation might involve a two-step mechanism—the first being the inhibition of signaling by binding of SOCS protein to an active complex and the second being disposal of those signaling components via proteasomal degradation. Recent work by Ram and Waxman supports this hypothesis, with results indicating that complete inhibition of GH signaling by CIS requires an active proteasomal degradation pathway [29 ].

Crosstalk mediated by SOCS proteins
Given the large number of cytokines capable of inducing SOCS protein expression, it is not surprising that a number of hypotheses have been made implicating SOCS proteins as the mediators of crosstalk inhibition by opposing cytokine-signaling pathways. For example, it has been shown that IL-3 can antagonize IL-6-type cytokine (e.g., IL-6 or IL-11)-driven B-lymphocyte development [65 , 66 ]. It has subsequently been shown that the addition of IL-3 to primary B-cell colonies inhibits IL-11-supported B-cell development by suppression of IL-11-induced STAT3 phosphorylation, which involves the synthesis of a protein within 30 min of IL-3 addition [53 ]. Analysis of IL-3-induced SOCS mRNA expression profiles has found that the SOCS-3 temporal expression pattern correlates well with the negative effects on STAT3 phosphorylation and might be responsible for this inhibition. The second example of crosstalk involves the state of GH resistance that develops during sepsis or inflammation, which has been attributed to the effects of IL-1ß production [67 , 68 ]. Recently, Boisclair and colleagues [44 ] found that IL-1ß induces SOCS-3 expression in primary hepatocytes and hepatic cell lines, but its expression pattern differs from that induced by GH in that its magnitude is significantly greater, and the expression is prolonged beyond 24 h after stimulation. This altered expression pattern has been shown to match the profile of IL-1ß-induced GH resistance, which requires 8–24 h to reduce GH-driven transcription of STAT5-responsive genes [44 ]. SOCS-3 has also been implicated in controlling macrophage responsiveness to IFN-{gamma} upon chronic exposure to bacterial lipopolysaccharide. Lipopolysaccharide induces SOCS-3 mRNA expression in macrophages, and transfection studies show that SOCS-3 suppresses IFN-{gamma}-mediated transcriptional responses [48 ]. Crosstalk using SOCS proteins might also explain the negative effects of IL-10 on cytokine signaling. IL-10 is capable of attenuating a range of inflammatory responses in immune cells [69 ], and it is considered to have negative effects on the actions of IFNs [70 ]. IL-10 has been shown to induce SOCS-3 mRNA expression, and it is thought to be capable of blocking IFN-{alpha}-induced STAT1 phosphorylation and subsequent gene transcription in monocytes [71 ].

SOCS knockout and transgenic models
Considerable information has been generated about CIS, SOCS-1, -2 and -3 mechanisms of action and their effects on cytokine signaling, but this information is clouded by the bewildering number of roles suggested for them from in vitro experiments. It was anticipated that genetic deletion studies might reveal insights into the physiological function(s) of these proteins.

SOCS-1
SOCS-1-/- mice are healthy at birth but die before weaning due to fatty degeneration of the liver, monocytic infiltration of organs, reduced thymus size, and significant loss of T- and B-lymphocytes [72 , 73 ]. In addition, deficits in lymphocyte numbers and selective depletion of maturing B-lymphoid cells have also been observed. SOCS-1-/- spleen weights are not significantly different from those of normal mice, but they are devoid of lymphoid follicles or composed of immature cells. It is interesting that the SOCS-1-/- phenotype is reminiscent of that induced by elevating IFN-{gamma} levels in neonatal mice [74 , 75 ]. Subsequent work has shown that the SOCS-1-deficient phenotype can be corrected with administration of antibodies against IFN-{gamma} or by crossing mice with IFN-{gamma}-/- mice [33 , 76 ], identifying IFN-{gamma} as an essential component in the manifestation of the phenotype. The hypothesis that SOCS-1 controls IFN-{gamma} sensitivity is strengthened by the fact that SOCS-1-/- macrophages have enhanced IFN-{gamma}-mediated killing of Leishmania parasites and a hyperresponsive reaction to viral infection [33 ]. These results support a model of hyperresponsiveness to IFN-{gamma}, but the phenotype is compounded by the fact that SOCS-1-/- mice also have elevated IFN-{gamma} levels, raising the question of the source of the excessive cytokine production. Reconstitution of irradiated JAK3-deficient mice with SOCS-1-/- bone marrow can confer the lethal SOCS-1-/- phenotype, implying that lymphocytes might mediate at least some of the phenotype. Strong support for this hypothesis is also obtained by crossing SOCS-1-/- mice with mice deficient in RAG2, resulting in a rescue of the phenotype in a manner similar to that when SOCS-1-/- mice are crossed with IFN-{gamma}-/- mice [76 ]. Taken together, these results indicate that SOCS-1 attenuates IFN-{gamma} signaling as well as playing a role in controlling the production of this cytokine.

Given the in vitro data suggesting a pleiotropic role for SOCS-1 in many signaling systems, it was somewhat surprising to find a limited, yet extremely potent role for SOCS-1 in regulating IFN-{gamma} signaling. However, there are now indications that other more subtle phenotypes could be present in the SOCS-1-/- mice. SOCS-1-/- embryonic fibroblasts have been shown to be more sensitive to tumor necrosis factor (TNF)-{alpha}, but the relevance of these findings is unclear at present [36 ]. In addition, these embryonic fibroblasts display enhanced insulin-induced differentiation into adipocytes, and mice devoid of SOCS-1 have significantly elevated levels of glucose [77 ]. These results suggest that SOCS-1 plays a role in regulating insulin signal transduction. The mechanism of this action is uncertain, but overexpression of SOCS-1 inhibits insulin-induced insulin receptor substrate-1 phosphorylation via blockade of JAK1 action [77 ]. Other lines of evidence also suggest that SOCS-1 might play additional physiological roles that are yet to be identified. Mice with transgenic overexpression of SOCS-1 in T cells have impaired IL-6 and IL-7 signaling in addition to inhibited IFN-{gamma} action. These mice also have reduced thymocyte populations, significantly increased CD4/CD8 ratios, and expression of activation markers in splenic T cells [78 ]. Together, these results imply that SOCS-1 plays a role in T-cell development and homeostasis. The relevance and importance of these findings are yet to be established, but the roles of SOCS-1 are beginning to be unraveled.

SOCS-2
Although the previously described SOCS members have clear physiological roles in the immune system, the recently generated SOCS-2-/- mice have no detectable defect in their hematopoietic systems. It was not until 6 weeks of age that male SOCS-2-deficient mice were found to be significantly larger than wild-type mice, manifesting a 40% increase in size by 12 weeks of age [79 ]. Most organs also become significantly larger but in proportion to the overall increase in size of these animals. Furthermore, the long bones and nose-to-tail lengths increase significantly in SOCS-2-deficient animals. Similar growth abnormalities have also been observed in female SOCS-2-deficient animals, although these are not quite as severe. Histological examinations of SOCS-2-/- animals have found a marked thickening of the dermis characterized by excessive collagen accumulation, as well as some collagen deposition in organ ducts and vessels. SOCS-2-/- mice have significantly lower levels of MUP (major urinary protein), a GH-pulsatile product that is down-regulated in mice lacking or overexpressing GH [80 ]. Insulin-like growth factor (IGF)-I production is also controlled to a certain extent by GH, but analysis of circulating IGF-I levels has failed to detect any significant difference in IGF-1 production between wild-type and SOCS-2-deficient animals. However, emerging models of GH/IGF-I induction indicate that local autocrine/paracrine production of IGF-I is more important for growth than circulating, liver-derived IGF-I [81 , 82 ]. RNase protection assays have been performed on a number of organs and have found significantly elevated levels of IGF-I mRNA in the heart, lung, and spleen but not in the bone, liver, fat, or muscle. These results indicate that SOCS-2 plays an important role in controlling some component(s) of postnatal growth, and there is evidence that the GH/IGF-I axis is a focus of its action.

SOCS-3
Ablation of SOCS-3 again demonstrates the important role SOCS proteins play in regulating cytokine signaling. SOCS-3-/- mice die between embryonic days 12 and 14 due to massive erythrocytosis surrounding the fetal liver and abdominal region, whereas overexpression of SOCS-3 completely blocks all fetal liver hematopoiesis [83 ]. Analysis of SOCS-3-/- progenitor cells has found that they are hyperresponsive to IL-3 and EPO, and although reconstitution of lethally irradiated wild-type mice with SOCS-3-/- fetal liver cells fails to identify any role for SOCS-3 in normal adult hematopoiesis, hematopoietic progenitors from these mice exhibit enhanced responsiveness to a number of cytokines [83 ]. Together, this work suggests that SOCS-3 plays a crucial role in limiting erythroid-lineage expansion.

Unfortunately, any potential role(s) of SOCS-3 in other signaling systems has not been evaluated because of the developmental block generated by the lethal phenotype, but it is hoped that future gene-targeting strategies using Cre/lox recombination and conditional gene targeting will bypass this impediment.

CIS
In contrast to the striking phenotypes of SOCS-1-, -2-, or -3-deficient mice, deletion of CIS fails to reveal any phenotypic changes in mice [83 ], and transgenic models are required for gaining any indications as to the physiological function of CIS. Enforced expression of CIS induces a phenotype similar to that observed with the STAT5a-/- and STAT5b-/- mice [84 85 86 ], encompassing incomplete mammary gland involution and reduced whey acidic protein expression, dwarfing/feminization of males, reduced levels of GH-induced MUP, suppression of STAT5 phosphorylation, and a reduced T cell response to IL-2 stimulation [87 ]. These mice also have significantly lower numbers of {gamma}{delta} T cells and natural killer, and natural killer-T cells. In addition, CIS-transgenic mice generated a significantly higher proportion of Th2 type T cells after T cell receptor stimulation, compared with wild-type mice. These findings strongly suggest that the physiological functions of CIS are to negatively regulate STAT5 contributions to growth, mammary gland function, and T cell development.

PIAS
The PIAS family of molecules was discovered in yeast two-hybrid screens designed to identify STAT-interacting proteins. Database searches with an interacting candidate molecule termed PIAS1, identified it to be part of a family of structurally related proteins that share a putative zinc-binding domain, a highly acidic region, and >50% homology at the amino acid level to other family members [88 ]. Unlike SOCS proteins, which are expressed upon cytokine stimulation, PIAS1 is constitutively expressed in a number of cell lines. However, overexpression studies discovered that PIAS1 binds only to activated STAT1 dimers and inhibits their DNA-binding activity, whereas monomeric forms of STAT1 are not bound [88 ]. Deletion studies with PIAS1 mutants defined a region in the C terminus of the protein that interacts with an N-terminal domain of the STAT1 dimer (called the STAT-interacting domain) [89 ], but no role has been ascribed to the putative zinc-binding domain.

Recent work investigating the regulation of STAT1 activity has further defined the nature of the STAT1/PIAS1 interaction. Mowen and colleagues [90 ] discovered that STAT1 dimers are methylated on a conserved arginine residue, a modification that greatly increases their ability to bind DNA and initiate gene transcription. With the use of methylation inhibitors, it was found that methylation prevents PIAS1 from binding to activated STAT dimers, whereas inhibition of methylation allows PIAS1 to freely interact with these dimers and inhibit their DNA binding and transcription actions. Cells which have been genetically altered to be incapable of breaking down methylation inhibitors that are normally generated in cells, and thus have high levels of methylation inhibitors, have been shown to have greatly reduced STAT1 DNA-binding activity because PIAS is capable of binding to a higher proportion of STAT1 dimers [90 ]. These observations might have important clinical applications given that some cancers lack the ability to regulate methylation inhibitor levels [91 ].

PIAS3 is constitutively expressed in a wide range of tissues and subsequently interacts specifically with phosphorylated STAT3 molecules in IL-6-stimulated M1 cells [92 ]. This phenomenon is also induced by other IL-6 type cytokines, and like PIAS1, PIAS3 activity ablates all STAT3-mediated gene transcription. Thus, two members of the PIAS family target specific STAT molecules to dampen their activities. The constitutive expression of these molecules implies that their physiological function differs from that of SOCS proteins, which are induced in a classical negative feedback loop on cytokine stimulation. Consequently, PIAS proteins may act like a buffer that titrates the concentration of active STAT dimers within the cell. However, most of the data compiled on PIAS function rely heavily on in vitro yeast two-hybrid and overexpression studies. Gene deletion studies in mice could be extremely informative in deciphering PIAS physiological functions, as they have been for the SOCS proteins.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 PHOSPHATASES
 SOCS
 CONCLUDING REMARKS
REFERENCES
 
The molecules reviewed here represent an integrated system by which cells can control the signaling initiated by cytokines (Fig. 2 ). They work at different levels of the signaling cascade, from inhibiting the receptor to blocking transcription factor activation. These regulatory proteins also act at different time points within a response to a cytokine-signaling cascade. Together, they provide a finely tuned regulation of important physiological processes. It is hoped that future genetic studies will further unravel the nature and mechanisms of their action and provide sufficient insight to allow future clinical modification of these processes.



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  		Figure 2. Mechanism of negative regulation of the JAK/STAT pathway. Cytokine binds to its receptor causing receptor dimerization and phosphorylation, leading to the recruitment of JAKs that cross-phosphorylate before phosphorylating the receptor. STAT molecules bind to phosphorylated docking sites, are in turn phosphorylated, dimerize, and enter the nucleus where they initiate transcription. Some of these genes activated are SOCS family members, which in turn bind and deactivate JAKs and occupy receptor STAT-binding sites. SHP-1 binds to the activated receptor before dephosphorylating the JAKs, and PIAS molecules bind to active STAT dimers preventing them from binding to DNA. Not shown are mechanisms for receptor complex internalization and degradation._art>

 


   ACKNOWLEDGEMENTS
 
This work is supported by the Anti-Cancer Council of Victoria, Melbourne, Australia; The National Health and Medical Research Council, Canberra, Australia; The National Institutes of Health, Bethesda, MD (grant CA-22556); and the Australian Federal Government Cooperative Research Centers Program.

Received April 24, 2001; revised May 31, 2001; accepted June 6, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PHOSPHATASES
 SOCS
 CONCLUDING REMARKS
 REFERENCES
 

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T. Ben-Zvi, A. Yayon, A. Gertler, and E. Monsonego-Ornan
Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling
J. Cell Sci., January 15, 2006; 119(2): 380 - 387.
[Abstract] [Full Text] [PDF]