Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers . All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 .

Cytokine signaling mediated by the JAK-STAT pathway plays essential roles in differentiation, maturation, proliferation and apoptosis of a various types of cells. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of the JAK-STAT signaling pathway. SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers . All SOCS share a central SH2 domain and a C-terminal SOCS box, but only SOCS1 and SOCS3 possess a kinase inhibitory region immediately upstream of the central SH2 .

suppressor of cytokine signaling 2 Enables insulin-like growth factor receptor binding activity; phosphorylation-dependent protein binding activity; and ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including growth hormone receptor signaling pathway; negative regulation of growth hormone receptor signaling pathway; and response to estradiol. Part of Cul5-RING ubiquitin ligase complex. Is active in cytoplasm. Implicated in endometrial cancer and ovarian carcinoma. Biomarker of ductal carcinoma in situ and invasive ductal carcinoma. This gene encodes a member of the suppressor of cytokine signaling (SOCS) family. SOCS family members are cytokine-inducible negative regulators of cytokine receptor signaling via the Janus kinase/signal transducer and activation of transcription pathway (the JAK/STAT pathway). SOCS family proteins interact with major molecules of signaling complexes to block further signal transduction, in part, by proteasomal depletion of receptors or signal-transducing proteins via ubiquitination. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10, interferon (IFN)-gamma and by cytokine receptors such as growth horomone receptor. The protein encoded by this gene interacts with the cytoplasmic domain of insulin-like growth factor-1 receptor (IGF1R) and is thought to be involved in the regulation of IGF1R mediated cell signaling. This gene has pseudogenes on chromosomes 20 and 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

Objective—Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction,

mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of

SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic

plaque development.

Methods and Results—Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by

vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared

to the fibrous area. SOCS were also increased in aortic lesions from apoE /  mice. In cultured VSMCs, endothelial

cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic

lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced

inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo,

antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE /  mice by

increasing the size, leukocyte content, and chemokine expression in the lesions.

Conclusions—SOCS expressed in atherosclerotic lesions are key regulators of vascular cell responses. Activation of this

endogenous antiinflammatory pathway might be of interest in the treatment of atherosclerosis.

SOCS-1 and SOCS-3 coprecipitates with JAK kinases upon IFNG stimulation and are able to inhibit the JAK-STAT pathway, although with different affinity and kinetics. SOCS1 and SOCS3 binds to phosphorylated JAK1/2 and prevent the tyrosine kinase activity of JAKs through their kinase inhibitory region (KIR), thereby inhibiting downstream IFNG signaling. SOCS1 may also prevent IFNG signaling by targeting the signaling machinery to ubiquitin-proteasomal degradation pathway.

Protein-Protein, Genetic, and Chemical Interactions for Ben-Zvi T (2006):Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. curated by BioGRID (https://thebiogrid.org); ABSTRACT: Fibroblast growth factor receptor (FGFR) signaling is transduced by the mitogen-activated protein kinase (MAPK) cascade and the signal transducers and activators of transcription (STATs). Suppressors of cytokine signaling (SOCS) proteins are expressed in response to cytokine-inducible stimulation of STAT phosphorylation, acting in a negative-feedback mechanism to hinder the activities of these receptors. However, there are no data concerning the role of SOCS proteins in the regulation of fibroblast growth factor receptor (FGFR) signaling. In the present study, we show that activation of FGFR in chondrocytes induces the expression of SOCS1 and SOCS3 mRNA, and that these proteins are constitutively associated with FGFR3, as demonstrated by co-immunoprecipitation studies. Transfection of cells with FGFR3-GFP and SOCS1-CFP revealed their colocalization, clustered prominently in the perinuclear cytosolic part of the cell. The effect of the interaction between FGFR3 and SOCS1 on receptor activity was investigated in a chondrocytic cell line overexpressing SOCS1. In these cells, STAT1 phosphorylation is repressed, MAPK phosphorylation is elevated and prolonged, and FGFR3 downregulation is attenuated. Expression of osteopontin (OPN), which is directly upregulated by FGF in chondrocytes, was stimulated by lower levels of FGF in cells expressing SOCS1 compared with parental cells. Blocking of MAPK phosphorylation by PD98059 decreased OPN expression in both cell types, but this decrease was more marked in cells expressing SOCS1. The presented results suggest a novel interaction between the SOCS1 and SOCS3 proteins and the FGFR3 signaling pathway.

Rainbow trout oligonucleotides used in this study.

Muscles of older animals are more susceptible to injury and regenerate poorly, in part due to a persistent inflammatory response. The janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory signaling and is tightly regulated by the suppressor of cytokine signaling (SOCS) proteins, especially SOCS3. SOCS3 expression is altered in the muscle of aged animals and may contribute to the persistent inflammation and impaired regeneration. To test this hypothesis, we performed myotoxic injuries on mice with a tamoxifen-inducible deletion of SOCS3 specifically within the muscle stem cell compartment. Muscle stem cell-specific SOCS3 deletion reduced muscle mass at 14 days post-injury (-14%, P < 0.01), altered the myogenic transcriptional program, and reduced myogenic fusion based on the number of centrally-located nuclei per muscle fiber. Despite the delay in myogenesis, muscles with a muscle stem cell-specific deletion of SOCS3 were still able to regenerate after a single bout or multiple bouts of myotoxic injury. A reduction in SOCS3 expression in muscle stem cells is unlikely to be responsible for the incomplete muscle repair in aged animals.

The Drosophila testis is a well-established system for studying stem cell self-renewal and competition. In this tissue, the niche supports two stem cell populations, germ line stem cells (GSCs), which give rise to sperm, and somatic stem cells called cyst stem cells (CySCs), which support GSCs and their descendants. It has been established that CySCs compete with each other and with GSCs for niche access, and mutations have been identified that confer increased competitiveness to CySCs, resulting in the mutant stem cell and its descendants outcompeting wild type resident stem cells. Socs36E, which encodes a negative feedback inhibitor of the JAK/STAT pathway, was the first identified regulator of niche competition. The competitive behavior of Socs36E mutant CySCs was attributed to increased JAK/STAT signaling. Here we show that competitive behavior of Socs36E mutant CySCs is due in large part to unbridled Mitogen-Activated Protein Kinase (MAPK) signaling. In Socs36E mutant clones, MAPK activity is elevated. Furthermore, we find that clonal upregulation of MAPK in CySCs leads to their outcompetition of wild type CySCs and of GSCs, recapitulating the Socs36E mutant phenotype. Indeed, when MAPK activity is removed from Socs36E mutant clones, they lose their competitiveness but maintain self-renewal, presumably due to increased JAK/STAT signaling in these cells. Consistently, loss of JAK/STAT activity in Socs36E mutant clones severely impairs their self-renewal. Thus, our results enable the genetic separation of two essential processes that occur in stem cells. While some niche signals specify the intrinsic property of self-renewal, which is absolutely required in all stem cells for niche residence, additional signals control the ability of stem cells to compete with their neighbors. Socs36E is node through which these processes are linked, demonstrating that negative feedback inhibition integrates multiple aspects of stem cell behavior.

suppressor of cytokine signaling 6 Predicted to enable signaling adaptor activity. Acts upstream of or within proteasomal protein catabolic process. Located in immunological synapse. The protein encoded by this gene contains a SH2 domain and a CIS homolog domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by GM-CSF and EPO in hematopoietic cells. A high expression level of this gene was found in factor-independent chronic myelogenous leukemia (CML) and erythroleukemia (HEL) cell lines. [provided by RefSeq, Jul 2008]

Protein-Protein, Genetic, and Chemical Interactions for Liau NPD (2018):The molecular basis of JAK/STAT inhibition by SOCS1. curated by BioGRID (https://thebiogrid.org); ABSTRACT: The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structural basis of both these modes of inhibition. Due to alterations within the SOCS box domain, SOCS1 has a compromised ability to recruit Cullin5; however, it is a direct, potent and selective inhibitor of JAK catalytic activity. The kinase inhibitory region of SOCS1 targets the substrate binding groove of JAK with high specificity and thereby blocks any subsequent phosphorylation. SOCS1 is a potent inhibitor of the interferon gamma (IFNγ) pathway, however, it does not bind the IFNγ receptor, making its mode-of-action distinct from SOCS3. These findings reveal the mechanism used by SOCS1 to inhibit signalling by inflammatory cytokines.

Chronic stress is a major factor in the poor growth and immune performance of salmonids in aquaculture. However, the molecular mechanisms linking stress effects to growth and immune dysfunction is poorly understood. The suppressors of cytokine signaling (SOCS), a family of genes involved in the inhibition of JAK/STAT pathway, negatively regulates growth hormone and cytokine signaling, but their role in fish is unclear. Here we tested the hypothesis that cortisol modulation of SOCS gene expression is a key molecular mechanism leading to growth and immune suppression in response to stress in fish. Exposure of rainbow trout (Oncorhynchus mykiss) liver slices to cortisol, mimicking stress level, upregulated SOCS-1 and SOCS-2 mRNA abundance and this response was abolished by the glucocorticoid receptor antagonist mifepristone. Bioinformatics analysis confirmed the presence of putative glucocorticoid response elements in rainbow trout SOCS-1 and SOCS-2 promoters. Prior cortisol treatment suppressed acute growth hormone (GH)-stimulated IGF-1 mRNA abundance in trout liver and this involved a reduction in STAT5 phosphorylation and lower total JAK2 protein expression. Prior cortisol treatment also suppressed lipopolysaccharide (LPS)-induced IL-6 but not IL-8 transcript levels; the former but not the latter cytokine expression is via JAK/STAT phosphorylation. LPS treatment reduced GH signaling, but this was associated with the downregulation of GH receptors and not due to the upregulation of SOCS transcript levels by this endotoxin. Collectively, our results suggest that upregulation of SOCS-1 and SOCS-2 transcript levels by cortisol, and the associated reduction in JAK/STAT signaling pathway, may be a novel mechanism leading to growth reduction and immune suppression during stress in trout.

suppressor of cytokine signaling 1 Enables kinase inhibitor activity. Involved in negative regulation of CD8-positive, alpha-beta T cell differentiation and positive regulation of CD4-positive, alpha-beta T cell differentiation. Acts upstream of or within several processes, including cell surface receptor signaling pathway; fat cell differentiation; and negative regulation of signal transduction. Predicted to be located in nucleoplasm. Is expressed in several structures, including brain; eye; genitourinary system; gut; and hemolymphoid system gland. Human ortholog(s) of this gene implicated in acute myeloid leukemia; gastrointestinal system cancer (multiple); reproductive organ cancer (multiple); and urinary bladder cancer. Orthologous to human SOCS1 (suppressor of cytokine signaling 1). PHENOTYPE: Homozygotes for targeted null mutations exhibit retarded growth, hyperresponsiveness to endogenous interferon gamma, hepatitis with fatty degeneration, lymphopenia due to excess apoptosis, monocytic organ infiltration, and lethality by 3 weeks of age. [provided by MGI curators]

Protein-Protein, Genetic, and Chemical Interactions for Callus BA (2002):SOCS36E, a novel Drosophila SOCS protein, suppresses JAK/STAT and EGF-R signalling in the imaginal wing disc. curated by BioGRID (https://thebiogrid.org); ABSTRACT: 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), d-stat (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.

The SOCS box domain was first identified in SH2-domain-containing proteins ofthe suppressor of cytokines signaling (SOCS) family but was latter alsofound in: - The WSB (WD-40-repeat-containing proteins with a SOCS box) family, - The SSB (SPRY domain-containing proteins with a SOCS box) family, - The ASB (Ankyrin-repeat-containing proteins with a SOCS box) family, - The RAR (GTPase domain and SOCS box-containing proteins) family .The SOCS box found in these proteins is a C-terminal domain of about 50 aminoacids composed of two blocks of well-conserved residues separated by between 2to 10 nonconserved residues . The C-terminal conserved region is aLeu/Pro-rich sequence of unknown function, whereas the N-terminal conservedregion is called a 'BC box' and binds to the elongin BC complex . Ithas been proposed that this association could couple bound proteins to theubiquitination or proteasomal compartments .Some proteins known to contain a SOCS box domain are listed below: - Mammalian cytokine-inducible SH2-containing (CIS) protein. This protein belongs to the SOCS family and inhibits erythropoietin and interleukin 3 receptor signaling by competing with signaling molecules such as STATs for binding to phosphorylated receptor cytoplasmic domains. - Mammalian SOCS-1 protein. This protein is a negative regulator of interleukin 6 signaling. It acts by binding to and inhibiting the catalytic activity of members of the JAK family of cytoplasmic kinases. - Vertebrate WSB-1.The profile we developed covers the entire SOCS box domain.

suppressor of cytokine signaling 4 Involved in negative regulation of epidermal growth factor-activated receptor activity. The protein encoded by this gene contains a SH2 domain and a SOCS BOX domain. The protein thus belongs to the suppressor of cytokine signaling (SOCS), also known as STAT-induced STAT inhibitor (SSI), protein family. SOCS family members are known to be cytokine-inducible negative regulators of cytokine signaling. Two alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Corticotroph SOCS-3 as an intracellular suppressor of cytokine signaling. Corticotroph SOCS-3 inhibits STAT-dependent POMC gene expression by negatively interfering with LIF-induced activation of the JAK-STAT cascade. In contrast, CRH-induced POMC gene expression is not affected by SOCS-3. LIF stimulation of the corticotroph results in rapid upregulation of SOCS-3 by a STAT-dependent mechanism. Thus, LIF-induced activation of corticotroph POMC gene activation is limited by parallel induction of SOCS-3 expression, rendering the cell resistant to further JAK-STAT activation. On the other hand, autoregulation of STAT-dependent SOCS-3 gene expression and rapid degradation of SOCS-3 protein by the proteasome pathway enable the cell to restore its functional status. LIF and CRH synergistically induce POMC promoter activity. LIF activates POMC promoter activity not only by direct binding of activated STATs, but also indirectly by inducing STAT-dependent expression of transcription factors c-fos and JunB. CRH also induces SOCS3 promoter activity by binding of c-fos and JunB. Thus, CRH indirectly inhibits LIF-induced POMC promoter activation and downregulates the synergistic cross-talk of CRH and LIF on POMC promoter activity. Adapted from ref. and ref. with permission.

suppressor of cytokine signaling 1 Enables insulin-like growth factor receptor binding activity and protein kinase binding activity. Involved in macrophage differentiation; negative regulation of receptor signaling pathway via JAK-STAT; and positive regulation of regulatory T cell differentiation. Located in nucleoplasm. Implicated in acute myeloid leukemia; gastrointestinal system cancer (multiple); reproductive organ cancer (multiple); and urinary bladder cancer. Biomarker of ductal carcinoma in situ; esophageal cancer (multiple); human immunodeficiency virus infectious disease; invasive ductal carcinoma; and respiratory system cancer (multiple). This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including IL2, IL3 erythropoietin (EPO), CSF2/GM-CSF, and interferon (IFN)-gamma. The protein encoded by this gene functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. Knockout studies in mice suggested the role of this gene as a modulator of IFN-gamma action, which is required for normal postnatal growth and survival. [provided by RefSeq, Jul 2008]

SOCS (suppressors of cytokine signaling) box of SOCS3-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS3, like CIS1 and SOCS1, is involved in the down-regulation of the JAK/STAT pathway. SOCS3 inhibits JAK activity indirectly through recruitment to the cytokine receptors. SOCS3 has been shown to play an essential role in placental development and a non-essential role in embryo development. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

AimsInterferon-γ (IFN-γ) exhibits hepatotoxicity through signal transducer and activator of transcription 1 (STAT1) activation. On the contrary, interleukin-11 (IL-11) shows tissue-protective effects on various organs including the liver through STAT3 activation. Here, we found that IL-11 pretreatment protects hepatocytes from IFN-γ-induced death and investigated the molecular mechanisms, particularly focusing on signal crosstalk.Methods and resultsPrimary culture mouse hepatocytes were treated with IL-11 prior to IFN-γ, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-γ-induced hepatocyte death. Since IFN-γ-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-γ robustly activated STAT1 with its peak at 1 hr after stimulation, which was significantly attenuated by IL-11 pretreatment. Consistently, IL-11 pretreatment impeded mRNA increase of STAT1-downstream molecules promoting cell death, i.e., IRF-1, caspase 1, bak, and bax. IL-11-mediated suppression of STAT1 signaling was presumably due to upregulation of the suppressor of cytokine signaling (SOCS) genes, which are well-known negative feedback regulators of the JAK/STAT pathway. Interestingly, however, IFN-γ pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-γ also upregulated SOCSs. Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers.ConclusionIL-11 protects hepatocytes from IFN-γ-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-γ/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes.