The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action
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Zhang, Jianguo; Metcalf, Donald; Rakar, Steven; Asimakis, Maria; Greenhalgh, Christopher J.; Willson, Tracy A.; Starr, Robyn; Nicholson, Sandra E.; Carter, Wendy; Alexander, Warren S.; Hilton, Douglas J.; Nicola, Nicos A.

doi:10.1073/pnas.231486498

Cited by 141 publications

(115 citation statements)

References 24 publications

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“…However, this was not the case. Our results are consistent with the observation that knock-in mice expressing a SOCS-box deficient SOCS-1 protein die of hyper-interferon-gamma (IFNg) sensitivity at a slower rate than SOCS-17/7 mice (Zhang et al, 2001). In this case, as well as SOCS-1, the SOCS-box is necessary for full activity in vivo.…”

Section: Discussionsupporting

confidence: 91%

SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc

2002

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We have cloned a novel SOCS gene from Drosophila, socs36E, which is most homologous to the mammalian socs-5 gene. Socs36E is expressed zygotically, predominantly during embryogenesis, in a highly dynamic pattern. In vivo expression of SOCS36E in transgenic flies results in several adult phenotypes. Engrailed-GAL4 directed expression causes loss of the wing anterior cross vein, humeral outgrowths, absence of halteres and eye pigmentation defects. Expression of SOCS36E under apterous-GAL4 control resulted in outstretched wings. Full penetrance of these phenotypes required the presence of the SH2 and SOCS-box domains of SOCS36E. The observed phenotypes were consistent with defects in JAK/STAT or EGF-R signalling and were exacerbated in flies heterozygous for either the d-jak (hopscotch), dstat (stat92E) or d-egf-r (der) genes. Conversely, inactivating one copy of the d-cbl gene, a negative regulator of the d-EGF-R, partially rescued the wing phenotypes. These genetic interactions imply that SOCS36E can suppress activities of the JAK/STAT and EGF-R signalling pathways in the wing disc and suggest that SOCS36E interacts with multiple pathways in vivo.

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Section: Discussionsupporting

confidence: 91%

SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc

2002

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“…We have recently identified SPSB2 as the adapter protein in an E3 ubiquitin ligase complex that ubiquitinates iNOS, targeting it for proteasomal degradation (19). The SOCS box is a sequence motif, first identified in SOCS proteins, which, in conjunction with elonginBC, recruits cullin-5 and Rbx-2 to form an active E3 complex (20,21). Ubiquitination involves the transfer of a ubiquitin molecule via an E1-E2-E3 enzyme cascade (22), where the E3 ligase functions as both a substrate recognition molecule and a catalyst for the transfer of ubiquitin to a lysine in the substrate protein (23).…”

Section: †mentioning

confidence: 99%

TLR Regulation of SPSB1 Controls Inducible Nitric Oxide Synthase Induction

Lewis

Kolesnik

Kuang

et al. 2011

The Journal of Immunology

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The mammalian innate immune system has evolved to recognize foreign molecules derived from pathogens via the TLRs. TLR3 and TLR4 can signal via the TIR domain-containing adapter inducing IFN-β (TRIF), which results in the transcription of a small array of genes, including IFN-β. Inducible NO synthase (iNOS), which catalyzes the production of NO, is induced by a range of stimuli, including cytokines and microbes. NO is a potent source of reactive nitrogen species that play an important role in killing intracellular pathogens and forms a crucial component of host defense. We have recently identified iNOS as a target of the mammalian SPSB2 protein. The SOCS box is a peptide motif, which, in conjunction with elongins B and C, recruits cullin-5 and Rbx-2 to form an active E3 ubiquitin ligase complex. In this study, we show that SPSB1 is the only SPSB family member to be regulated by the same TLR pathways that induce iNOS expression and characterize the interaction between SPSB1 and iNOS. Through the use of SPSB1 transgenic mouse macrophages and short hairpin RNA knockdown of SPSB1, we show that SPSB1 controls both the induction of iNOS and the subsequent production of NO downstream of TLR3 and TLR4. Further, we demonstrate that regulation of iNOS by SPSB1 is dependent on the proteasome. These results suggest that SPSB1 acts through a negative-feedback loop that, together with SPSB2, controls the extent of iNOS induction and NO production.

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“…The suppressor of cytokine signaling (SOCS) 3 proteins function as part of a classical negative feedback loop, attenuating cytokine action through inhibition of the Janus kinase/signal transducers and activators of transcription signal transduction pathway (1). The SOCS proteins comprise an N-terminal region, a central SH2 domain, and a conserved C-terminal motif of ϳ40 amino acids, termed the SOCS box.…”

mentioning

confidence: 99%

“…Structural and functional analyses have shown that SOCS proteins mediate their effects by direct interaction with activated Janus kinases and cytokine receptors via their N-terminal and SH2 domains (2). Recent in vivo evidence has revealed, however, that for a complete termination of signal transduction, the SOCS box is also required (3).…”

mentioning

confidence: 99%

Ankyrin Repeat and Suppressors of Cytokine Signaling Box Protein Asb-9 Targets Creatine Kinase B for Degradation

Debrincat

Zhang

Willson

et al. 2007

Journal of Biological Chemistry

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The suppressors of cytokine signaling (SOCS) proteins inhibit cytokine action by direct interaction with Janus kinases or activated cytokine receptors. In addition to the N-terminal and Src homology 2 domains that mediate these interactions, SOCS proteins contain a C-terminal SOCS box. DNA data base searches have identified a number of other protein families that possess a SOCS box, of which the ankyrin repeat and SOCS box-containing (Asb) proteins constitute the largest. Although it is known that the SOCS proteins are involved in the negative regulation of cytokine signaling, the biological and biochemical functions of the Asbs are largely undefined. Using a proteomics approach, we demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme. The suppressor of cytokine signaling (SOCS)3 proteins function as part of a classical negative feedback loop, attenuating cytokine action through inhibition of the Janus kinase/signal transducers and activators of transcription signal transduction pathway (1). The SOCS proteins comprise an N-terminal region, a central SH2 domain, and a conserved C-terminal motif of ϳ40 amino acids, termed the SOCS box. Structural and functional analyses have shown that SOCS proteins mediate their effects by direct interaction with activated Janus kinases and cytokine receptors via their N-terminal and SH2 domains (2). Recent in vivo evidence has revealed, however, that for a complete termination of signal transduction, the SOCS box is also required (3).The SOCS box was first identified in the SOCS proteins and has since been found in more than 50 proteins across a range of species (4, 5). These proteins have been subdivided into nine different families based on the type of domain or motif they possess upstream of the SOCS box and include the eight SOCS proteins, 18 Asbs (ankyrin repeat-containing SOCS box proteins), four SSBs (SPRY-domain proteins with a SOCS box), and two WSBs (WD40 repeat proteins with a SOCS box) (4, 5). The SOCS box from several of these family members binds Elongin C, which in turn associates with a complex consisting of Elongin B, a cullin family member (Cullin-2 or Cullin-5), and a RING finger protein called Roc1 or Rbx1 (5-7). This protein complex constitutes an E3 ubiquitin ligase termed the ECS (Elongin C-cullin-SOCS box) that, together with a ubiquitinactivating enzyme (E1) and a ubiquitin-conjugating enzyme (E2), facilitates the polyubiquitylation and proteasomal degradation of bound proteins, thereby regulating protein levels within the cell (8, 9). Other studies suggest an additional role for the SOCS box, in particular that the SOCS box-Elongin B/C interaction may act to stabilize SOCS proteins, thereby protecting SOC...

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The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo

Cited by 141 publications

References 24 publications

SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc

SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc

TLR Regulation of SPSB1 Controls Inducible Nitric Oxide Synthase Induction

Ankyrin Repeat and Suppressors of Cytokine Signaling Box Protein Asb-9 Targets Creatine Kinase B for Degradation

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