SOCS6 (Suppressor Of Cytokine Signaling 6)
2014-05-01 Julhash U Kazi , Amilcar Flores-Morales , Lars Rönnstrand AffiliationDivision of Translational Cancer Research, Lund Stem Cell Center, Lund University, Lund, Sweden (JUK, LR); Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (AFM)
Identity
HGNC
LOCATION
18q22.2
LOCUSID
ALIAS
CIS-4,CIS4,HSPC060,SOCS-4,SOCS-6,SOCS4,SSI4,STAI4,STATI4
Abstract
The suppressor of cytokine signaling (SOCS) family of proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of two structural motifs: a centrally located SH2 domain and a SOCS box in the C-terminus. The SOCS box mediates the interaction with the Elongins B and C complex while an additional motif mediates its interaction with Cullin 5 to assemble a Cullin\/Ring ubiquitin ligase. In this complex SOCS6 acts as a substrate recognition subunit through interactions mediated by the N-terminus and the SH2 domain. SOCS6 interacts with tyrosine kinase receptors FLT3 and c-KIT and modulate their ubiquitination and function.
DNA/RNA
Figure 1: SOCS6 mapped on Human Dec. 2013 (GRCh38/hg38) assembly in chromosome 18: (70288901-70330198) spanning 41298 base pairs using UCSC Genome Browser.
Description
According to Entrez-Gene SOCS6 maps to NC_000018.10 in the region between 70288901 and 70330199 on the plus strand. According to UCSC genome browser SOCS6 has two exons, one shorter of 190 base pairs and other on of 5656 base pairs.
Transcription
SOCS6 mRNA has 5864 nucleotides (NM_004232.3). The open reading frame (ORF) includes 1608 nucleotides situated in exon 2 (Figure 1). Transcription is induced by activation of certain cytokine receptors and growth factor receptors.
Pseudogene
Chromosome 11q14.1 has a SOCS6 pseudogene in between 83789973 and 83791578 spanning 1606 base pairs. The pseudogene has a 92% sequence similarity with the SOCS6 gene.
Proteins
Description
SOCS6 gene is expressed as an approximately 60 kDa protein with calculated isoelectric point 6.83 and total charge -0.76 at pH 7. SOCS6 has a still uncharacterized long N-terminal region, an SH2 domain and a C-terminal SOCS-box (Figure 2). The protein is mainly expressed in the cytosol and associates with multiple proteins (Bayle et al., 2004; Bayle et al., 2006; Hwang et al., 2007; Kazi et al., 2012; Zadjali et al., 2011). Most relevant for SOCS6 function is its capacity to associate with Elongin B and Elongin C and with Cullin 5 to assemble a functional E3 ubiquitin ligase complex.
Figure 2: Domain structure of SOCS6 protein, SB stand for SOCS-box.
Expression
SOCS6 is highly to moderately expressed in heart, parathyroid, salivary gland, stomach, thyroid, kidney and skeletal muscle tissues. Expression was also reported in mature hematopoietic cells and melanocyte.
Localisation
SOCS6 predominantly localizes to the cytosol and nucleus (Hwang et al., 2007). The N-terminal amino acids 1-210 influence its nuclear localization. Additionally SOCS6 localizes to the mitochondria and probably to the inner-surface of cell membrane (Lin et al., 2013).
Function
SOCS6 is involved in protein destabilization and to some extent acts as a signaling molecule. The presence of multiple domains in SOCS6 protein facilitates interaction with multiple signaling molecules. The SOCS6 SH2 domain associates with specific tyrosine phosphorylated proteins and the SOCS-box recruits the ubiquitin machinery directing proteins for degradation (Kazi et al., 2014; Zadjali et al., 2011).
Homology
Homologous proteins are found in various species including monkey, mouse, rat, frog and zebra fish etc. Monkey SOCS6 displays as high as 98% sequence similarity to human SOCS6, while zebra fish SOCS6 display 68% sequence similarity. In any case, the SOCS-box sequence is highly conserved and maintains a 100% sequence similarity.
Mutations
Note
In the COSMIC database 52 different SOCS6 mutations have been listed, where 40 mutations are non-synonymous (figure 3), two mutations introduce stop codons at 199 and 328 sites, one mutation is reported as a 254A and 255G deletion and the other 9 mutations are synonymous mutations.
Figure 3: Mutations in SOCS6 protein according to COSMIC database.
Implicated in
Entity name
Hepatocellular carcinoma
Note
SOCS6 expression is significantly reduced in hepatocellular carcinoma and lower SOCS6 correlates with overall and disease free survival (Qiu et al., 2013).
Entity name
Lung squamous cell carcinoma
Note
Loss of SOCS6 function is associated with poor prognosis in primary lung squamous cell carcinoma. Copy number loss and slight hyper-methylation that was correlated with disease progression was reported in this disease (Sriram et al., 2012).
Entity name
Prostate cancer
Note
The down-regulation of SOCS6 has been reported in prostate cancer tissues with a higher Gleason score, the advanced pathological stage, positive metastasis, and the positive PSA failure suggesting that SOCS6 might be associated with aggressive progression of prostate cancer (Zhu et al., 2013).
Entity name
Gastric cancer
Note
Loss of SOCS6 function has been reported in gastric cancer. Allelic loss and promoter hyper-methylation occur in this cancer. Ectopic expression of SOCS6 led to reduced cell growth and colony formation of gastric cancer cell (Lai et al., 2010).
Entity name
Pancreatic cancer
Note
The microRNA miR-424-5p is a suppressor of SOCS6 expression. This microRNA is up-regulated in pancreatic cancer resulting in down-regulation of SOCS6 (Wu et al., 2013). Down-regulation of SOCS6 led to increased proliferation, migration and invasion of pancreatic cancer cells suggesting SOCS6 acts as a tumor suppressor in pancreatic cancer.
Entity name
Glucose metabolism
Note
SOCS6 has been shown to interact with the insulin receptor (INSR), INSR substrates IRS2 and IRS4, and negatively regulates insulin signaling (Krebs et al., 2002; Mooney et al., 2001). Although these findings suggest that SOCS6 might play a role in glucose metabolism, mice lacking SOCS6 gene did not display any significant defects in glucose metabolism apart from a slight growth retardation (Krebs et al., 2002).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 14707129 | 2004 | Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. | Bayle J et al |
| 16643902 | 2006 | The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. | Bayle J et al |
| 17603019 | 2007 | The nuclear localization of SOCS6 requires the N-terminal region and negatively regulates Stat3 protein levels. | Hwang MN et al |
| 24705897 | 2014 | SOCS proteins in regulation of receptor tyrosine kinase signaling. | Kazi JU et al |
| 22952242 | 2012 | Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. | Kazi JU et al |
| 12052866 | 2002 | SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation. | Krebs DL et al |
| 19646809 | 2010 | SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation. | Lai RH et al |
| 22955947 | 2013 | Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation. | Lin HY et al |
| 11342531 | 2001 | Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. | Mooney RA et al |
| 23475171 | 2013 | Reduced expression of SOCS2 and SOCS6 in hepatocellular carcinoma correlates with aggressive tumor progression and poor prognosis. | Qiu X et al |
| 22363434 | 2012 | Array-comparative genomic hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma. | Sriram KB et al |
| 23653113 | 2013 | MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer. | Wu K et al |
| 21030588 | 2011 | Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase. | Zadjali F et al |
| 23666742 | 2013 | Expression of SOCSs in human prostate cancer and their association in prognosis. | Zhu JG et al |
Other Information
Locus ID:
NCBI: 9306
MIM: 605118
HGNC: 16833
Ensembl: ENSG00000170677
Variants:
dbSNP: 9306
ClinVar: 9306
TCGA: ENSG00000170677
COSMIC: SOCS6
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37972389 | 2024 | Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways. | 4 |
| 38766781 | 2024 | Publisher Correction: MiR-21 and miR-183 can simultaneously target SOCS6 and modulate growth and invasion of hepatocellular carcinoma (HCC) cells. | 0 |
| 37972389 | 2024 | Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways. | 4 |
| 38766781 | 2024 | Publisher Correction: MiR-21 and miR-183 can simultaneously target SOCS6 and modulate growth and invasion of hepatocellular carcinoma (HCC) cells. | 0 |
| 35038704 | 2022 | MicroRNA-494-3p Exacerbates Renal Epithelial Cell Dysfunction by Targeting SOCS6 under High Glucose Treatment. | 3 |
| 35907010 | 2022 | Methyltransferase-like 3 facilitates lung cancer progression by accelerating m6A methylation-mediated primary miR-663 processing and impeding SOCS6 expression. | 6 |
| 35038704 | 2022 | MicroRNA-494-3p Exacerbates Renal Epithelial Cell Dysfunction by Targeting SOCS6 under High Glucose Treatment. | 3 |
| 35907010 | 2022 | Methyltransferase-like 3 facilitates lung cancer progression by accelerating m6A methylation-mediated primary miR-663 processing and impeding SOCS6 expression. | 6 |
| 33589592 | 2021 | Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6. | 13 |
| 33689885 | 2021 | Inhibition of SOCS6 confers radioresistance in esophageal squamous cell carcinoma. | 1 |
| 33710445 | 2021 | Circ_0085289 Alleviates the Progression of Periodontitis by Regulating let-7f-5p/SOCS6 Pathway. | 10 |
| 34100174 | 2021 | Inhibition of miR-1298-5p attenuates sepsis lung injury by targeting SOCS6. | 10 |
| 34895274 | 2021 | Down-regulation of SOCS6: an unfavorable prognostic factor for gastrointestinal stromal tumor proven by survival analysis. | 0 |
| 33589592 | 2021 | Circular RNA circ_103820 suppresses lung cancer tumorigenesis by sponging miR-200b-3p to release LATS2 and SOCS6. | 13 |
| 33689885 | 2021 | Inhibition of SOCS6 confers radioresistance in esophageal squamous cell carcinoma. | 1 |
Citation
Julhash U Kazi ; Amilcar Flores-Morales ; Lars Rönnstrand
SOCS6 (Suppressor Of Cytokine Signaling 6)
Atlas Genet Cytogenet Oncol Haematol. 2014-05-01
Online version: http://atlasgeneticsoncology.org/gene/42351/socs6-(suppressor-of-cytokine-signaling-6)
