SUPPRESSOR OF CYTOKINE SIGNALING 3
| SOCS3 |
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SOCS3SUPPRESSOR OF CYTOKINE SIGNALING 3
Entrez Gene: 9021
HUGO Accession: HGNC:19391
OMIM (Online Mendellian Inheritance in Man)
Suppressor of cytokine signaling (SOCS) proteins are key regulators of immune responses and exert their effects in a classic negative-feedback loop. SOCS3 is transiently expressed by multiple cell lineages within the immune system and functions predominantly as a negative regulator of cytokines that activate the JAK (see 147795)-STAT3 (102582) pathway (summary by Hill et al., 2010).
Minamoto et al. (1997) isolated a human cDNA encoding SSI3 (STAT-induced STAT inhibitor-3) from a Jurkat cDNA library based on its sequence similarity and hybridization to a mouse Ssi1 probe. The SSI3 gene encodes a deduced 225-amino acid protein. Masuhara et al. (1997) isolated the same gene and referred to it as CIS3 (cytokine-inducible SH2 protein-3). Starr et al. (1997) referred to the gene as SOCS3 (suppressor of cytokine signaling-3).
Masuhara et al. (1997) showed that CIS3 bound to the JAK2 (147796) tyrosine kinase domain.
Using macrophages obtained from Soc3-deficient mice, Yasukawa et al. (2003) observed that IL10 (124092) or IL6 suppressed Tnf (191160) and Il12 (see 161561) production after lipopolysaccharide stimulation. These results suggested that SOCS3 selectively blocks signaling by IL6.
Lang et al. (2003) reported that phosphorylation of Stat3 is prolonged after IL6, but not IL10, stimulation in Socs3-deficient macrophages. They concluded that SOCS3 prevents the activation of an IFN-induced program of gene expression.
He et al. (2003) reported the identification of frequent hypermethylation in CpG islands of the functional SOCS3 promoter that correlated with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary lung cancer tissue samples. Restoration of SOCS3 in lung cancer cells where SOCS3 was methylation-silenced resulted in the downregulation of active STAT3 (102582), induction of apoptosis, and growth suppression. These results suggested that methylation silencing of SOCS3 is one of the important mechanisms of constitutive activation of the JAK/STAT pathway in cancer pathogenesis. The data also suggested that SOCS3 therapy may be useful in the treatment of cancer.
Spangenburg (2005) found that Socs3 mRNA level and transcriptional activity increased during differentiation in a mouse myoblast cell line. Socs3 expression was induced, at least in part, by activation of insulin-like growth factor-1 receptor (IGF1R; 147730) during differentiation. Overexpression of Socs3 cDNA increased transcription of reporter genes activated by skeletal muscle alpha-actin (see 102610) and serum response factor (SRF; 600589) promoters during myoblast differentiation, but it did not affect transcription from an Nfat (see NFAT1; 600489) promoter. Socs3 contributed to myoblast differentiation in the absence of Igf1 (147440), suggesting that SOCS3 activation is downstream of IGF1 signaling.
Jo et al. (2005) created cell-penetrating (CP) forms of murine Socs3 by adding membrane-translocating motifs to either the N- or C-terminal ends of the Socs3 protein. Both recombinant CP-Socs3 proteins distributed to multiple organs in mice within 2 hours following intraperitoneal injection and persisted for at least 8 hours in leukocytes and lymphocytes. CP-Socs3 protected mice from the lethal effects of staphylococcal enterotoxin B and lipopolysaccharide by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. CP-Socs3 also reduced concavalin A-induced liver apoptosis. Jo et al. (2005) concluded that replenishing intracellular stores of SOCS3 with CP-SOCS3 suppresses the effects of acute inflammation.
Using microarray analysis and quantitative real-time PCR, Sonkoly et al. (2007) showed that expression of miR203 (MIRN203; 611899) was consistently upregulated in psoriatic skin lesions (see 177900) compared with normal skin. In situ hybridization revealed increased expression of miR203 in all epidermal layers of psoriatic lesional skin. Sonkoly et al. (2007) identified an evolutionarily conserved putative 10-nucleotide miR203-binding site in the 3-prime UTR of SOCS3. Immunohistochemical analysis showed that expression of SOCS3 protein was complementary to that of miR203, with higher SOCS3 expression in the basal layer of keratinocytes in healthy skin and suppression of SOCS3 in the dermis of psoriatic lesions. Western blot analysis confirmed downregulation of SOCS3 in psoriasis. Quantitative real-time PCR showed no significant difference in SOCS3 mRNA expression in psoriatic and healthy skin, suggesting that downregulation of SOCS3 in psoriasis occurs at the posttranscriptional level. Since SOCS3 deficiency leads to sustained activation of STAT3 in response to IL6 (147620), a cytokine present in psoriatic lesions, Sonkoly et al. (2007) proposed that suppression of SOCS3 by miR203 in psoriatic lesions leads to constant STAT3 activation.
Ma et al. (2007) stated that Hnf1b (189907) knockout in mouse kidney results in cyst formation. Using genomewide chromatin immunoprecipitation and DNA microarray analysis and microarray analysis of mRNA expression, Ma et al. (2007) identified Socs3 as an Hnf1b target gene in mouse kidney. Hnf1b bound to the Socs3 promoter and repressed Socs3 transcription. Expression of Socs3 increased in Hnf1b-knockout mice and in renal epithelial cells expressing dominant-negative mutant Hnf1b. Increased levels of Socs3 inhibited Hgf (142409)-induced tubulogenesis by decreasing phosphorylation of Erk (see MAPK1; 176948) and Stat3. Conversely, knockdown of Socs3 in renal epithelial cells expressing dominant-negative mutant Hnf1b rescued the defect in Hgf-induced tubulogenesis by restoring phosphorylation of Erk and Stat3. Ma et al. (2007) concluded that HNF1B regulates renal tubulogenesis by controlling expression of SOC3.
Sabio et al. (2008) explored the mechanism of JNK1 (601158) signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1 deficiency in adipose tissues suppressed high-fat diet-induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine IL6 by adipose tissue caused increased expression of liver SOCS3, which induces hepatic insulin resistance. Sabio et al. (2008) concluded that JNK1 activation in adipose tissue can cause insulin resistance in the liver.
Babon et al. (2006) described the solution structure of murine Socs3 in complex with a phosphotyrosine-containing peptide from the Il6 receptor signaling subunit gp130 (IL6ST; 600694). The structure of the complex showed that 7 residues form a predominantly hydrophobic binding motif. Regions outside the Socs3 SH2 domain were important for ligand binding; in particular, a 15-residue alpha helix immediately N-terminal to the SH2 domain made direct contacts with the phosphotyrosine binding loop and, in part, determined its geometry. The SH2 domain itself contains a 35-residue unstructured PEST motif that increased Socs3 turnover.
For discussion of a possible association between variation in the SOCS3 gene and atopic dermatitis, see ATOD4 (605805).
During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is erythropoietin (EPO; 133170) independent. Marine et al. (1999) found that transgene-mediated expression in mice blocked fetal erythropoiesis, resulting in embryonic lethality. Homozygous deletion of the Socs3 gene in mice resulted in embryonic lethality at 12 to 16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors was greatly increased. Socs3-deficient fetal liver stem cells could reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in Jak3 (600173)-deficient mice also occurred normally. These results demonstrated that SOCS3 is critical in negatively regulating fetal liver hematopoiesis.
Roberts et al. (2001) generated mice lacking a functional Socs3 gene. They showed that the death of Socs3 -/- mice at midgestation is not related to defects in the embryo but is associated with abnormalities in specific regions of the placenta. They concluded that lethality in Socs3-null mice results from placental insufficiency and found no evidence of defective erythropoiesis.
Takahashi et al. (2003) found that Socs3-deficient placentas had reduced spongiotrophoblasts and increased trophoblast secondary giant cells. Overexpression of Socs3 in a trophoblast stem cell line suppressed giant cell differentiation. Conversely, Socs3-deficient trophoblast stem cells differentiated more readily to giant cells in culture. Leukemia inhibitory factor (LIF; 159540) promoted giant cell differentiation in vitro, and Lif receptor (LIFR; 151443) deficiency resulted in loss of giant cell differentiation in vivo. Lifr deficiency rescued the Socs3-deficient placenta defect and embryonic lethality. Takahashi et al. (2003) concluded that SOCS3 is an essential regulator of LIFR signaling in trophoblast differentiation.
Croker et al. (2003) used conditional gene targeting to generate mice lacking Socs3 in liver and macrophages. They found that IL6 (147620) induced prolonged activation of Stat1 (600555) and Stat3 (102582) in Soc3 -/- cells, whereas IFNG (147570) induced normal activation. Conversely, Stat activation was normal in Socs1-deficient cells after IL6 stimulation but prolonged after IFNG stimulation. Microarray analysis showed that the gene expression pattern in livers of Soc3-deficient mice after IL6 injection resembled that of normal mice injected with IFNG. Croker et al. (2003) concluded that SOCS3 and SOCS1 have reciprocal functions in IL6 and IFNG regulation and that SOCS3 may have a role in preventing IFNG-like responses in cells stimulated by IL6.
Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS3 is predominantly expressed in T-helper type 2 cells, and Seki et al. (2003) investigated its role in TH2-related allergic diseases. They found a strong correlation between SOCS3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. Socs3 transgenic mice showed increased TH2 responses and multiple pathologic features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant Socs3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased TH2 development. These data indicated that SOCS3 has an important role in regulating the onset and maintenance of TH2-mediated allergic immune disease, and suggested that SOCS3 may be a new therapeutic target for antiallergic drugs.
Chen et al. (2006) used a conditional knockout approach to examine the effect of Socs3 on T-helper (Th) cell polarization in mice. They found that Socs3 had little effect on Th1 or Th2 polarization, but it had a significant role in constraining generation of Th17 cells, the subset of Th cells that selectively produce Il17 (603149) and are putative regulators of inflammation. Il23 (see 605580)-induced phosphorylation of Stat3 was enhanced in Th cells lacking Socs3. Chromatin immunoprecipitation and PCR analysis showed that Stat3 bound to both the Il17 and Il17f (606496) promoters and that the binding was enhanced by stimulation with Il23. RT-PCR, ELISA, and flow cytometric analysis demonstrated increased Il17 expression in the absence of Socs3. Stimulation with Tgfb (190180) and Il6 potently induced Il17 secretion, and this stimulation was enhanced in the absence of Socs3. Chen et al. (2006) concluded that SOCS3 plays an important role in Th cell differentiation by limiting development of Th17 cell polarization through attenuation of phosphorylation of Stat3, which is likely to be a direct regulator of IL17 transcription.
Wong et al. (2006) found that a mouse model of rheumatoid arthritis (RA; 180300) induced by methylated bovine serum albumin and Il1 (see 147760) was exacerbated in mice lacking Socs3 in hematopoietic and endothelial cells. The enhanced inflammatory arthritis in mutant mice was associated with marked bone destruction and increased osteoclast and neutrophil infiltration. Neutrophil numbers were also increased in blood, spleen, and bone marrow. Serum levels of Il6 and Gcsf (CSF3; 138970) were elevated, and draining lymph nodes were enlarged and contained hyperproliferative T cells producing Il17. Macrophages from mutant mice were also hyperresponsive to Il1. Wong et al. (2006) concluded that SOCS3 is a critical negative regulator of IL1-dependent acute inflammatory arthritis and osteoclast generation.
Hill et al. (2010) studied the contribution of Socs3 to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. They found that grafts from mice lacking Socs3 only in hematopoietic cells had an augmented capacity to induce acute GVHD. Transplantation with donors in which Socs3 deficiency was restricted either to myeloid or T-cell lineages showed that acute GVHD mortality with gastrointestinal pathology occurred only in grafts from Socs3-deficient T-cell donors. T cells lacking Socs3 underwent enhanced alloantigen-dependent proliferation and produced Il10, Il17, and Ifng after stem cell transplantation, although acute GVHD induction was dependent only on Ifng. In addition, Socs3-deficient donor T cells induced severe Tgfb (190180)- and Ifng-dependent sclerodermatous GVHD. Hill et al. (2010) proposed that delivery of small SOCS3 mimetics may be useful in the inhibition of both acute and chronic GVHD.
Smith et al. (2009) found that knockout of Socs3 in retinal ganglion cells promoted neuronal survival and permitted regeneration of the optic nerve following crush injury. Double knockout of gp130 (IL6ST; 600694) and Socs3 blocked axon regeneration after injury, suggesting that Socs3 inhibits a gp130-dependent signaling pathway. Ciliary growth factor (CNTF; 118945) was upregulated following nerve injury, and intravitreous injection of Cntf further enhanced axon regeneration in Socs3-knockout mice.
HPRD (Human Protein Reference Database)
Proteins Linked to SOCS3: 26