Suppressors of cytokine signaling (SOCS): negative regulators of ...

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Warren S. Alexander, Robyn Starr, Donald Metcalf, Sandra E. Nicholson, Alison Farley,. Andrew G. Elefanty, Marta Brysha, Benjamin T. Kile, Rachel Richardson, ...

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction Warren S. Alexander, Robyn Starr, Donald Metcalf, Sandra E. Nicholson, Alison Farley, Andrew G. Elefanty, Marta Brysha, Benjamin T. Kile, Rachel Richardson, Manuel Baca, Jian-Guo Zhang, Tracy A. Willson, Elizabeth M. Viney, Naomi S. Sprigg, Steven Rakar, Jason Corbin, Sandra Mifsud, Ladina DiRago, Dale Cary, Nicos A. Nicola, and Douglas J. Hilton The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Victoria, Australia

Abstract: SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokinedependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1-/- mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1-/- mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects. J. Leukoc. Biol. 66: 588–592; 1999. Key Words: JAK · STAT

INTRODUCTION The interaction between the four alpha-helical bundle cytokines and their specific cell-surface receptors triggers the activation of intracellular signal transduction pathways that induce a range of biological responses. Despite the plethora of known cytokines and the wide diversity of physiological processes they influence, several recurring themes characterize the cytoplasmic signals they generate. Each of these cytokines specifically binds and induces the dimerization of members of the hemopoietin receptor family. These receptors are defined by 588

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the presence of an extracellular domain that contains conserved pairs of cysteine residues and a characteristic Trp-Ser-Xaa-TrpSer pentapeptide motif [1]. Although these receptors lack intrinsic tyrosine kinase activity, their dimerization results in the activation of intracellular kinases and a significant increase in the number of tyrosine-phosphorylated proteins [2]. Key mediators of this response are the JAK proteins, a family of four tyrosine kinases that associate with the cytoplasmic domains of hemopoietin receptors and become active on receptor oligomerization. The JAK kinases directly activate signaling molecules and phosphorylate tyrosine residues within the receptor intracellular domain, which creates docking sites for the recruitment and activation of additional signaling components that contain SH2 or other phosphotyrosine-binding motifs. Through these mechanisms, several key signaling cascades are typically activated. Specific members of the signal transducers and activators of transcription (STAT) family become phosphorylated, leading to their dimerization and translocation to the nucleus, where they influence gene expression directly or through the induction of expression of other transcription factors. The Ras/MAP kinase pathway may also be activated, usually initially via recruitment of Shc or Grb2 to the activated receptor. Often, changes in intracellular calcium concentration and alterations to lipid metabolism also are observed. Ultimately, changes in cell behavior are induced, including effects on survival, proliferation, maturation, and functional activation. Although the rapid and robust activation of signaling pathways is necessary for cytokine action, in order to appropriately control the magnitude and duration of cellular responses it is equally important for cells to be able to terminate these signals. Relatively little is understood of how such negative regulatory mechanisms operate. Molecules known to modulate signaling responses have been identified, including the tyrosine phosphatases and the protein inhibitors of activated STATs (PIAS), and the importance of a proper balance between positive and negative signals is demonstrated in the moth-eaten mouse, which lacks the phosphatase SHP-1. In these mice, cytokine responses are inappropriately regulated, resulting in the hyper-

Correspondence: Warren S. Alexander, Ph.D., The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia. E-mail: [email protected] Received March 16, 1999; revised May 4, 1999; accepted May 5, 1999.

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proliferation of cells of several hemopoietic lineages and the onset of autoimmunity [3]. Recently, a new family of negative regulators of cytokine signaling was identified. In our own laboratory, suppressor of cytokine signaling-1 (SOCS-1) emerged from an expression cloning screen for molecules capable of inhibiting interleukin (IL)-6-mediated differentiation of M1 myelomonocytic cells [4]. SOCS-1 is an SH2-domain-containing protein that was independently identified via its capacity to interact with JAK2 in a two-hybrid screen ( Janus kinase binding protein, JAB [5]) and also based on antigenic crossreactivity with STAT3 (STAT-induced STAT inhibitor, SSI [6]). The predicted amino acid sequence of SOCS-1 showed significant similarity to the cytokine-inducible SH2-containing protein (CIS [7]). In general, the expression of CIS and SOCS-1 mRNA is negligible in unstimulated cells, but can be induced rapidly on exposure to a range of cytokines [4, 6, 7]. Once expressed, both SOCS-1 and CIS inhibit cytokine signals, but via apparently divergent mechanisms. SOCS-1 can directly interact with JAK kinases and inhibit their catalytic activity [5, 6, 8, 9], whereas CIS binds to the activated cytokine receptor, competing with STATs for access to docking sites [7]. A role for SOCS proteins in regulating tyrosine kinase receptors has also been raised by studies suggesting that SOCS-1 inhibits c-Kit signaling via interactions with Grb2 or Vav [10]. Thus, SOCS proteins appear to act in a classical negative feedback loop to suppress signal transduction from cytokine receptors.

THE SOCS FAMILY OF PROTEINS Comparison of the predicted SOCS-1 amino acid sequence with the databases revealed the existence of a family of related proteins. In addition to SOCS-1 and CIS, six other mammalian sequences were identified, SOCS-2 to SOCS-7, that contained

an SH2 domain and shared a conserved 40-amino-acid carboxylterminal domain called the SOCS box [11]. Several additional families of SOCS box-containing proteins also were identified that exhibited alternative domains in place of SH2 motifs. These include proteins with ankyrin repeats (ASB-1 to ASB-4), WD-40 motifs (WSB-1 and WSB-2), SPRY domains (SSB-1 to SSB-3), or GTPase-like domains located upstream of the conserved SOCS box (Fig. 1) [11]. To determine whether other SOCS proteins shared the capacity of SOCS-1 to inhibit IL-6 signaling, we expressed cDNAs for CIS, SOCS-2, SOCS-3, and SOCS-5 in M1 myelomonocytic cells. Like SOCS-1, constitutive expression of SOCS-3 eliminated IL-6 and LIF-mediated clonal suppression and morphological differentiation of M1 cells. In contrast, SOCS-2 and SOCS-5 did not prevent IL-6 signaling, although M1 cells expressing these proteins did show slightly reduced sensitivity to cytokine. Constitutive expression of CIS in M1 cells had no effect on IL-6- or LIF-induced differentiation [8]. To explore the biochemical mechanisms through which SOCS-1 and SOCS-3 act, we examined the influence of these proteins on STAT3 activation, which is required for IL-6induced M1 differentiation [12, 13]. Whereas STAT3 was phosphorylated rapidly in unmanipulated, SOCS-2-, or SOCS5-expressing M1 cells on exposure to LIF or IL-6, no significant activation was observed in cells expressing SOCS-1 or SOCS-3 [8]. Thus, STAT3 tyrosine phosphorylation correlated with the capacity of SOCS proteins to inhibit M1 differentiation, strongly implying that SOCS-1 and SOCS-3 inhibit signaling in these cells via effects on the JAK-STAT pathway. Indeed, SOCS-1 has been shown to directly interact with and inhibit the activity of JAK family kinases [5, 6, 8]. However, when JAK1 or JAK2 were transiently expressed with SOCS-3, no inhibition of kinase activity was evident [8]. Thus, although both SOCS-1 and SOCS-3 clearly act on the JAK-STAT pathway, they appear

Fig. 1. The SOCS box motif is found in five families of proteins. SOCS family members (SOCS-1 to SOCS-7 and CIS) contain an SH2 domain upstream of the SOCS box, as well as a relatively non-conserved amino-terminal domain. Other families exhibit alternative domains in place of SH2 motifs, including ankyrin repeats (ASB-1 to ASB-4), WD-40 motifs (WSB-1 and WSB-2), SPRY domains (SSB-1 to SSB-3), or GTPase-like domains located upstream of the conserved SOCS box motif.

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likely to do so via distinct biochemical mechanisms. This was further emphasized in structure-function studies (see below), which revealed that although mutation of a conserved SH2 domain residue in SOCS-1 prevented inhibitory activity, the analogous change in SOCS-3 had no adverse effect. Alterations at different sites of the SOCS-3 SH2 phosphotyrosine binding loop were required to inhibit activity [8].

FUNCTIONAL ACTIVITIES OF SOCS PROTEIN DOMAINS The SOCS proteins can be considered to have three domains: a carboxyl-terminal SOCS box that is shared with other family members, a central SH2 motif, and a divergent amino-terminal domain of variable length [11]. To define which domains contribute to the capacity of SOCS proteins to inhibit signal transduction, a series of simple molecular truncation experiments were performed. As alluded to above, an intact SH2 domain is essential for the activity of both SOCS-1 and SOCS-3. However, although the SOCS-1 SH2 domain alone is capable of binding the tyrosine kinase domains of JAK proteins, in isolation it cannot effectively inhibit enzyme activity or prevent the actions of IL-6 or LIF [7, 8, 14]. The amino-terminal domain of SOCS proteins also is required. Truncation analysis suggests that the 20–30 amino acids immediately upstream of the SH2 domain are necessary, in conjunction with the SH2 domain, for SOCS-1 and SOCS-3 to effectively inhibit signal transduction [8, 14]. Within this amino-terminal domain sub-region, amino acid residues are conserved between SOCS-1 and SOCS-3, and analysis of the activities of chimeric proteins suggests that the amino-terminal domains of these SOCS proteins are interchangeable [8]. Co-immunoprecipitation studies provided evidence that under some circumstances the SOCS-1 amino-terminal domain may associate independently with JAK kinases [8]. These studies have begun to dissect the important issue of the biochemistry of SOCS action. They show that both SOCS-1 and SOCS-3 inhibit cytokine signaling by interfering with the activation of the JAK-STAT pathway. Although the function of both proteins requires the concerted action of their SH2 and amino-terminal domains, there are clear biochemical differences that characterize their activity. Although the carboxyl-terminal SOCS box is conserved in all family members, it appears to be dispensable for the inhibition of cytokine signals. Deletion of the SOCS box in mutant versions of SOCS-1 or SOCS-3 caused little or no alteration in biological activity [8, 14]. However, recent studies suggest that the SOCS box is a key regulator of protein turnover, both in the SOCS proteins as well as other families containing this motif. The sequence of the SOCS box shows similarity to regions of the von Hippel-Lindau tumor suppressor protein and elongin A, both of which are known to interact with elongins B and C [15]. Our own work and that of others has clearly shown that the SOCS box also interacts with elongins B and C and that this interaction is a feature of proteins from the SOCS, SSB, ASB, WSB, and GTPase-like families [15, 16]. There remains some controversy over the biological ramifications of the SOCS box-elongins interaction. Kamura and colleagues propose that SOCS protein half-life is extended on interaction with elongins 590

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[15]. Our own interpretation proposes that SOCS proteins may act as adaptors that link activated signaling molecules to proteasomal degradation. Elongin B contains a ubiquitin-like sequence that can interact directly with proteasomal proteins, and data have shown that SOCS-3 does undergo proteasomalmediated degradation [16]. Similarly, CIS has recently been shown to be ubiquitinated and sensitive to proteasomal degradation [17]. Because cytokine receptors and members of the JAK-STAT pathway exhibit sustained activation in the presence of proteasomal inhibitors [17, 18], it is feasible that the SOCS proteins control responses to cytokines by targeting these signaling molecules for degradation. This model implies that, contrary to observations (see above), deletion of the SOCS box would render cells hyper-responsive to cytokine. However, most of the analyses of the contribution of the SOCS box to protein activity utilized assays in which the SOCS proteins and other signaling molecules were significantly overexpressed and thus potentially capable of escaping physiological regulation. It is likely that the precise function of the SOCS box will only become clear when further analyses are performed under more physiological conditions.

BIOLOGICAL ROLES OF SOCS PROTEINS Although the biochemistry of SOCS protein action is beginning to be revealed, the biological roles of these regulators in vivo are unknown. To address this issue, we are utilizing gene targeting techniques to generate mice unable to produce SOCS proteins. The first of these to be analyzed are mice lacking SOCS-1 [19]. SOCS-1-/- mice were born in numbers expected from a Mendelian segregation of alleles and appeared normal during the first few days of life. However, by 10 days of age, the SOCS-1deficient animals were clearly smaller than their normal littermates and they quickly became ill and died during the second or third week of life. Histological analysis revealed a fatty degeneration of the liver that often extended throughout the entire organ and was sufficiently severe to account for the death of the mice. In contrast to the healthy livers of normal young mice, which contained typical focal aggregates of hemopoietic cells, the diseased SOCS-1-/- livers also were characterized by focal and generalized infiltration of immature and maturing granulocytes and monocytes. In addition, monocytic infiltration was observed in the pancreas, heart, and lungs. The absence of SOCS-1 in vivo also resulted in severe lymphoid deficiencies. Unlike normal littermates, in which circulating lymphocyte numbers gradually increased from birth, a progressive depletion of peripheral blood lymphocytes was evident in SOCS-1-/- mice. The thymus in these mice was small and was composed largely of medullary thymocytes, and the relative numbers of lymphocytes in the bone marrow and spleen were considerably lower than normal. Cell surface marker analysis using flow cytometry and antibodies to CD4 and CD8 indicated that the reduction in thymocytes was not the result of a selective depletion of a particular subset of cells. In contrast, immature B lineage cells appeared to be produced in relatively normal numbers, with a selective loss of more mature pre-B and B cells. When pre-B cells were grown in vitro, those derived from SOCS-1-/- mice were capable of differentiating into http://www.jleukbio.org

mature B cells with wild-type efficiency. Thus, the lymphoid deficiencies that characterize mice lacking SOCS-1 may reflect the loss of cells rather than developmental abnormalities. It is significant that the cells most sensitive to loss or damage in SOCS-1-/- mice are those that are known to express the gene. Our previous Northern blot studies had shown that SOCS-1 was expressed in lymphoid tissues as well as in the liver after cytokine stimulation [4, 11]. The incorporation of a ␤-galactosidase marker gene into the targeted SOCS-1 locus allowed us to confirm this expression pattern in SOCS-1⫹/- mice [19]. Thus, the lymphocyte deficiency and degeneration of the liver parenchyma is likely to be the direct result of the loss of critical SOCS-1 functions within these cells. Given the observation that STAT1 activation occurs constitutively in the livers of SOCS-1-/mice [19], we propose that the disease in these animals arises through the incapacity of lymphocytes and liver cells to control signals from cytokines with toxic side effects. We are currently pursuing the involvement of interferon-␥, the overexpression of which is known to cause liver damage and lymphocyte depletion [20, 21]. Indeed, recent studies have shown that SOCS-1 is inducible by interferon-␥ and can inhibit interferon signaling [our own unpublished data and ref. 22]. Naka and colleagues have also noted the lymphopenia in mice lacking SOCS-1 (SSI-1) and report elevated levels of the apoptosis regulator Bax in the spleen and thymus of these mice [23]. These studies also raise the possibility that SOCS-1 prevents apoptosis of lymphocytes by inhibiting Bax expression. The in vivo role of SOCS-1 in myeloid cells also remains to be fully clarified. In addition to the monocytic and granulocytic invasion of multiple organs in SOCS-1-/- mice, a variable elevation in circulating granulocytes was also observed [19]. Preliminary evidence suggests that granulocyte-macrophage progenitor cells in SOCS-1-/- mice may be hyper-responsive to the proliferative effects of cytokines. If SOCS-1-deficient granulocytes and macrophages also have an increased sensitivity to functional activation, they may contribute to the tissue damage that afflicts mice lacking this regulator.

CONCLUSIONS The SOCS family is a new group of intracellular molecules implicated in the negative regulation of cellular responses to cytokines. Important differences in specificity of SOCS action have emerged from our studies: for inhibition of IL-6 and LIF signaling, SOCS-1 and SOCS-3 have potent activity, whereas SOCS-2, SOCS-5, and CIS have little or no impact. Moreover, whereas both SOCS-1 and SOCS-3 act by preventing cytokinedependent activation of the JAK-STAT pathway, the biochemical mechanisms by which they function diverge. It now will be important to determine whether signaling cascades triggered by other cytokines are sensitive to SOCS action and to define whether specific SOCS proteins act as key regulators of individual cytokine responses. In addition, more extensive analysis to define precisely the biochemical mechanisms by which individual SOCS proteins act will also be required. Our gene knockout studies imply that the inhibitory actions of SOCS proteins on cytokine signaling, which were primarily defined biochemically and in cell culture studies, are indispens-

able to the regulation of multiple cell types in vivo. The further characterization of SOCS-1-/- mice and future revelations of the biological roles of other family members through gene targeting will define these critical functions in a physiological setting. It is feasible that abnormalities in SOCS function could contribute to human diseases in which cytokine responses are involved, possibly including infection, autoimmunity, and cancer. The accumulating data on the biochemistry and biology of SOCS action ultimately should provide the framework for assessing whether alterations to SOCS function contribute to disease.

ACKNOWLEDGMENTS This work was supported by the National Health and Medical Research Council, Canberra, the Anti-Cancer Council of Victoria, an Australian Government Cooperative Research Centres Program Grant, National Institutes of Health (Bethesda, MD) Grant No. CA22556, the J. D. and L. Harris Trust, and AMRAD Operations Pty Ltd, Melbourne.

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