|Coordinate||95,413,081 bp (GRCm38)|
|Base Change||C ⇒ A (forward strand)|
|Gene Name||suppressor of cytokine signaling 2|
|Synonym(s)||CIS2, D130043N08Rik, cytokine-inducible SH2 protein 2, STAT-induced STAT inhibitor 2, Cish2, SOCS-2, JAB, SSI-2|
|Chromosomal Location||95,385,362-95,417,180 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] 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]
PHENOTYPE: Mutations in this gene cause accelerated postnatal growth. Homozygotes for a targeted mutation also show increased bone growth, enlargement of most organs, collagen deposition in the skin and some ducts and vessels, lower major urinary protein levels, and elevated IGF-I mRNA levels in some tissues. [provided by MGI curators]
|Amino Acid Change||Glutamic Acid changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000020215] [ENSMUSP00000113378] [ENSMUSP00000117576] [ENSMUSP00000118720] [ENSMUSP00000117785] [ENSMUSP00000129331] [ENSMUSP00000131875]|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E10*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
AA Change: E57*
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9754|
|Is this an essential gene?||Probably nonessential (E-score: 0.213)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.433; ML prob: 0.438; human score: 0.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||2019-09-04 9:47 PM by Bruce Beutler|
|Record Created||2014-12-23 8:11 PM by Jeff SoRelle|
The samson phenotype was identified among N-nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1617, some of which showed increased body weights compared to their littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 82 mutations. The increased body weight phenotype was linked to a mutation in Socs2: a G to T transversion at base pair 95,413,081 (v38) on chromosome 10, or base pair 4,173 in the GenBank genomic region NC_000076 encoding Socs2. Linkage was found with a recessive model of inheritance (P = 1.231 x 10-6), wherein 3 variant homozygotes departed phenotypically from 7 homozygous reference mice and 10 heterozygous mice (Figure 2). The mutation corresponds to residue 631 in the mRNA sequence NM_145223 within exon 3 of 3 total exons.
The mutated nucleotide is indicated in red, and converts glutamine 57 of the SOCS2 protein to a stop codon.
|Illustration of Mutations in
Gene & Protein
Socs2 encodes suppressor of cytokine signaling 2 [SOCS2; alternatively, cytokine-inducible Src homology 2 (SH2)-containing protein (CIS)-2 or STAT-induced Stat-inhibitor-2 (SSI-2)], a member of the SOCS protein family. There are eight known members of the SOCS family including SOCS1-SOCS7 and CIS. Each member of the SOCS family has a variable length N-terminus, a central SH2 domain, and a highly conserved C-terminal SOCS-box motif [Figure 3 & 4; (1;2); PDB:2C9W].
The SH2 domain of SOCS2 (amino acids 46-135) is required for SOCS2 function and is proposed to bind to tyrosine phosphorylated sites of JAK kinases (see the record mount_tai for information about JAK3), cytokine receptors, growth hormone receptors, and STATS (see the record for domino for information about STAT1) after cytokine stimulation (1-4). N-terminal to the SH2 is the extended SH2 subdomain (ESS) (5). Although the mechanism is unclear, deletion of the ESS inhibits SOCS2-mediated regulation of the growth hormone receptor (4).
The SOCS-box (amino acids 154-195 in SOCS2) is essential for the inhibitory functions of SOCS2 (4). The SOCS-box can interact with Elongin B and C to form a complex with members of the Cullin and Rbx families (4;6;7). The SOCS2-Elongin B/C complex functions as an E3 ubiquitin ligase that targets proteins for polyubiquitination and subsequent proteasomal-mediated degradation (8). The SOCS2-Elongin B/C complex has been crystallized (PDB:2C9W) (5). The ESS is formed from a single amphipathic helix. N-terminal to the ESS is not predicted to have secondary structure (9). The ESS packs alongside the C-terminus and forms hydrophobic interactions with the SH2 domain and electrostatic interactions with the SOCS-box (5). The SH2 domain has a classic phosphotyrosine pocket (5). The SOCS-box has three core helices (H1-H3) that pack together with the H4 helix of Elongin B/C into a four-helix cluster. The H1 helix of SOCS2 is buried into a deep cleft between the Elongin C loop 5 and H4. The C-terminus of SOCS2 is buried in the interface between the SH2 domain and the SOCS-box.
The samson mutation (E57*) is within the SH2 domain. The expression and function of SOCS2samson have not been examined.
Socs2 is highly expressed in fetal kidney, adult heart, skeletal muscle, pancreas, and liver (10). The SOCS2 protein is highly expressed in the heart, lung, placenta, skeletal muscle, and peripheral blood lymphocytes (1). Between embryonic day 10 and postnatal day 8, SOCS2 is highly expressed in neural progenitor cells and neurons (11;12).
Socs2 expression is induced by cytokines and other factors (Table 1). See (13) for a comprehensive list of hormones and cytokines that regulate Socs2 expression.
Table 1. Factors that regulate Socs2 expression
Cytokines regulate growth, differentiation, metabolism, and the immune system. Upon receptor binding, cytokines activate the JAK (Janus kinase)-STAT pathway (Figure 5). The cytokine receptors are associated with JAK tyrosine kinases, which are normally dephosphorylated and inactive. Receptor stimulation results in dimerization/oligomerization and subsequent apposition of JAK proteins, which are now capable of trans-phosphorylation as they are brought in close proximity. This activates JAKs to phosphorylate the receptor cytoplasmic domains, creating phosphotyrosine ligands for the SH2 domains of STAT proteins. Once recruited to the receptor, STAT proteins are also tyrosine phosphorylated by JAKs, a phosphorylation event which occurs on a single tyrosine residue that is found at around residue 700 of all STATs. Tyrosine phosphorylation of STATs may allow formation and/or conformational reorganization of the activated STAT dimer, involving reciprocal SH2 domain-phosphotyrosine interactions between STAT monomers. Although STAT activation downstream of cytokine receptors in the JAK-STAT pathway is the best studied, STATs may also be activated by other means, including growth factor receptors [e.g. epidermal growth factor (EGF; see the record for Velvet) and platelet-derived growth factor (PDGF) receptors] potentially through the function of the Src nonreceptor tyrosine kinase, and by G-protein coupled seven-transmembrane receptors (21-23). Phosphorylated, activated STATs enter the nucleus and accumulate there to promote transcription (24). For more information on JAK-STAT signaling, see the record for domino.
Termination of STAT signaling requires ending both transcriptional activation and cytoplasmic STAT signaling. Protein tyrosine phosphatases including SHP1 (see the record for styx) and SHP2 prevent further cytoplasmic STAT tyrosine phosphorylation (25;26). SOCS proteins are recruited to active receptor complexes to induce inhibition. The SOCS proteins can directly bind and suppress JAKs or can compete with STATs for receptor binding (27;28). The inhibitory function of SOCS2 is dependent both on competitive binding via its SH2 domain and on SOCS2-mediated ubiquitination and proteasomal-mediated degradation by functioning in the SOCS2-Elongin B/C E3 ubiquitin ligase complex.
SOCS2 has several purported functions including the regulation of growth, metabolism, central nervous system development, cancer, and response to infection through either the positive or negative regulation of several signaling pathways including the GH receptor (GHR), insulin growth factor (IGF)-I receptor, prolactin, IL-2, IL-3, EPO receptor (EPOR), LIF, epidermal growth factor receptor (EGFR), IFN–α, leptin receptor (LEPR), FMS-like tyrosine kinase 3 (FLT3), and aryl hydrocarbon receptor (AhR)-dependent signaling pathways [Table 2; reviewed in (13)]. Several functions of SOCS2 are described in more detail, below.
Table 2. SOCS2 regulates several signaling pathways.
Abbreviations: GHR, growth hormone receptor; IGF-IR, insulin growth factor-I receptor; LEPR, leptin receptor; IL-2, interleukin-2; IL-3, interleukin-3; LIF, leukemia inhibitory factor; IFN–α, interferon-alpha; AhR, aryl-hydrocarbon receptor; LXAR, LXR alpha (alternatively, nuclear receptor subfamily 1, group H, member 3 (NR1H3); Pyk2, PTK2 protein tyrosine kinase 2 beta; TLR4, toll-like receptor 4; NGF, nerve growth factor; EPOR, erythropoietin receptor, EGFR, epidermal growth factor receptor; FLT3, FMS-like tyrosine kinase 3
SOCS2 function in GHR signaling
Growth hormone receptor (GHR) signaling regulates postnatal longitudinal growth, stimulates differentiation and mitogenesis, and modulates lipid, nitrogen, and mineral metabolism. The GHR signals through the JAK2/STAT5b signaling pathway (Figure 6). Upon binding of GH to the GHR, the GHR dimerizes and activates JAK2, which recruits STAT5. STAT5 dimerizes and translocates to the nucleus where it regulates the transcription of several target genes including those that encode IGF-I, IGF binding protein 3 (IGFBP3), SOCS1, SOCS2, and SOCS3, and CIS. GHR-associated signaling can also activate ERK (see the record for wabasha) through SRC, phospholipase C (PLC)γ (see the record for queen), and RAS, or by JAK2 via SH2-domain containing transforming protein (SHC), growth factor receptor-bound protein (GRB), and son of sevenless (SOS).
SOCS2 has a dual effect on GH-associated signaling by inhibiting the signaling at low concentrations, but stimulating signaling when highly expressed (29;30). SOCS2 interacts with the growth hormone receptor (GHR) and negatively regulates GHR-associated signaling by mediating the ubiqutination and proteasomal degradation of the GHR (4;7;30). SOCS2 binding to the GHR may also block the association between the GHR and positive regulators (4;5;41). SOCS2 may block access of STAT5 to the activated GHR; SOCS2 binds Tyr595 on the GHR, a known binding site for STAT5 (42).
SOCS2 regulates normal intestinal growth by limiting the actions of GH and/or GH-induced IGF-I on intestinal epithelial cell proliferation and mucosal growth (16). In Caco-2 cells, SOCS2 overexpression inhibited cell proliferation and promoted differentiation. In addition, in IEC-6 cells, GH induced SOCS2 expression, but reduced basal or IGF-I-induced proliferation. In isolated crypts from Socs2-/- mice, GH did not reduce the proliferative activity as observed in wild-type crypts.
Socs2-/- mice exhibit a 30-50% increase in body weight and length by 12 weeks of age (30;43-45). The increased growth was less marked in the female mice in that the females attained the weight of wild-type male mice on average (44). The increase body weights in the Socs2-/- mice is not due increased fat tissue, but due to a proportional enlargement of bone and muscle tissue as well as increased internal organ size and an increase in body length (44;46). The trabecular and cortical volumetric bone mineral density in the Socs2-/- mice is reduced compared to wild-type mice (47). The increased organ weights was due to elevated cell numbers rather than increased cell size (44). The Socs2-/- mice exhibit changes in major urinary protein levels, thickening of dermal layers due to collagen deposition, and elevated Igf1 mRNA in some tissues including heart, lungs, and spleen (44).
High growth (hg) mice have a spontaneous 500 Kb deletion within chromosome 10 affecting intron 2 of Socs2 as well as Raidd/Cradd (caspase and RIP adaptor with death domain) and Plexin C1 (viral encoded semaphorin receptor) (48;49). The two deletion breakpoints reside within intron 2 of both Socs2 and Plexin C1, leading to the formation of a Socs2-Plexin C1 fusion transcript (48). The hg mice exhibit a similar phenotype to the Socs2-/- mice in that they exhibit a 30-50% increase in postweaning growth, an increase in skin collagen content, increased organ and skeletal growth, and an increase in muscle mass (45;50;51). The hg mice have increased levels of plasma IGF-I with a concomitant decrease in plasma and pituitary GH (52).
Transgenic mice that overexpress SOCS2 (SOCS2-TG) also exhibit a mild excessive growth phenotype (30).
SOCS2 has several functions in neurons. SOCS2 regulates the differentiation of neural progenitor cells into neurons and blocks GH-associated inhibition of neural progenitor cell differentiation by blocking GH-mediated downregulation of neurogenin-1 (NGN-1) (11). Socs2-/- mice have decreased neuronal density and NGN1-expressing cells in the cortex and a reduction in the number of neural stem cells (11).
SOCS2 is a regulator of nerve growth factor (NGF) signaling (34). NGF binds to the tropomyosin receptor kinase A (TrkA) receptor to promote neuronal survival and neurite extension (34). Neuronal survival is promoted through the inhibition of apoptosis signaling through the activation of PI3K and AKT. Ras-mediated signaling and PLC activate the MAP kinase pathway to stimulate proliferation. The level of SOCS2 expression is proportional to the degree of neurite outgrowth in cortical neurons and differentiated neurospheres. SOCS2-TG exhibited increased neurite outgrowth. Differentiated neurospheres from the SOCS2-TG mice had more neurons with more complex processes (36;53). Increased SOCS2 expression resulted in NGF-dependent neurite outgrowth and increased TrkA receptor surface localization in dorsal root ganglion neurons and PC12 cells with a concomitant increased activation of pAKT and pERK1/2 (34). Socs2-/- mice had reduced neurite numbers and neurite length (36).
SOCS2 binds to epidermal growth factor receptor (EGFR) and results in the phosphorylation of EGFR to regulate neurite outgrowth; see the record Velvet for information about EGFR-related signaling (36;54). SOCS2 and EGFR promote both primary neurite number and neurite length in an EGFR kinase- and Src kinase-dependent manner (54). SOCS2 mediates these effects by competing with SHP2 for binding to the EGFR.
SOCS2 has immune-related functions. Socs2-/- mice exhibit decreased microbial proliferation, production of proinflammatory cytokines, leukocyte infiltration, and high mortality upon infection (18). Socs2-/- mice exhibit abnormal leukcoyte infiltration, uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, and increased mortality upon infection. The number of peripheral platelets, lymphocytes, monocytes, neutrophils and eosinophils was normal in the Socs2-/- mice (44). The Socs2-/- mice had increased inflammatory signaling in the liver and adipose tissues (55). The expression of IL-6, IFN-γ, RANTES (CCL5), iNOS, and NOX were increased in the livers of the high fat diet (HFD)-fed Socs2-/- mice compared to the HFD-fed wild-type mice (55). In the liver, phosphorylation of p65 NF-κB was increased and IκBα levels were decreased in the Socs2-/- mice; both were exacerbated with the HFD (55). The levels of IFN-γ, CCL2, and IL-1β were higher in adipose tissues of the Socs2-/- mice compared to HFD-fed wild-type mice (55). Socs2-/- mice exhibited elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology in atopic dermatitis and allergen (OVA)-induced airway inflammation models compared to wild-type mice (56). SOCS2 expression in activated CD4+ T cells can regulate IL-2 and IL-3 signals (32). CD4+ T cells from Socs2-/- mice have increased IL-4, IL-5, and IL-13 production as well as CD4+ T helper 2 (Th2) differentiation compared to those from wild-type mice. In addition, the SOCS2−/− CD4+ T cells have increased SOCS3- and IL-4-induced STAT6, but reduced IL-6-induced STAT3 phosphorylation compared to wild-type CD4+ T cells (56).
During IL-15-mediated NK priming, SOCS2 interacts with and ubiquitinates phosphorylated proline-rich tyrosine kinase 2 (Pyk2) to promote the proteasome-mediated degradation of Pyk2 and subsequent NK effector functions (14). RNA interference (RNAi)-mediated knockdown of SOCS2 resulted in compromised natural killer (NK) cell effector functions including IL-15-primed NK cell cytotoxicity and IFN-γ production (14). Loss of SOCS2 expression did not have an impact on IL-15 receptor signaling, IL-15-mediated NK cell differentiation, or IL-15-dependent NK cell survival (14).
SOCS1 and SOCS3 are known to negatively regulate TLR signaling in macrophage and DC maturation (57;58). SOCS2 is a feedback inhibitor of TLR-induced DC maturation and activation (19). In DCs, SOCS2 is a TLR-responsive gene. IL-10 and IL-1β expression was increased upon silencing of SOCS2 expression in DCs (19). In addition, IL-10-independent STAT3 phosphorylation was increased in SOCS2-deficient DCs (19). SOCS2-deficient immature DCs stimulated with lipopolysaccharide (LPS), a TLR4 ligand, failed to express CD83, a marker of DC maturation. In addition, the expression of co-stimulatory molecules CD40 (see the record for walla), CD86, and the MHC class II receptor HLA-DR on the stimulated cells was reduced. Silencing of SOCS2 resulted in reduced TLR4-associated MyD88-dependent and –independent signaling including a reduction in LPS-inducible genes encoding TNF-α (see the record for PanR1), IL-6, IL-1β, CCL-4, INF-β, CXCL-9 and CXCL-10 (59). SOCS2 deficiency also results in a decrease in LPS-induced NF-κB nuclear translocation (see the record for Finlay) (60), the phosphorylation of IRF3 (61), and the activation of MAP kinases (62). In dendritic cells, SOCS2 also targets TNFR-associated factors 2 and 6 for proteasome-mediated degradation (18).
Mutations in SOCS2 have been linked to increased susceptibility to type 2 diabetes in the Japanese population (63).
Similar to the hg and Socs2-/- mice, samson mice exhibit an increase in body weights, indicating a loss of function of the SOCS2samson protein, if expressed. Other SOCS2-related functions in samson have not been examined.
1) 94°C 2:00
The following sequence of 548 nucleotides is amplified (chromosome 10, - strand):
1 gccttggtaa actttaactc acaggcttta aaaaaaaaaa aaaaaggtgt aacaagagaa
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
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30. Greenhalgh, C. J., Metcalf, D., Thaus, A. L., Corbin, J. E., Uren, R., Morgan, P. O., Fabri, L. J., Zhang, J. G., Martin, H. M., Willson, T. A., Billestrup, N., Nicola, N. A., Baca, M., Alexander, W. S., and Hilton, D. J. (2002) Biological Evidence that SOCS-2 can Act either as an Enhancer Or Suppressor of Growth Hormone Signaling. J Biol Chem. 277, 40181-40184.
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|Science Writers||Anne Murray|
|Authors||Zhe Chen, Jeff SoRelle, Noelle Hutchins|