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SOCS6 (Suppressor Of Cytokine Signaling 6)

Written2014-05Julhash U Kazi, Amilcar Flores-Morales, Lars Rönnstrand
Division 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)

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.

Keywords CIS4; SSI4; CIS-4; SOCS4; STAI4; SOCS-4; SOCS-6; STATI4; HSPC060.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSOCS4
suppressor of cytokine signaling 4
Alias_symbol (synonym)CIS4
SSI4
HSPC060
STATI4
STAI4
Cish4
Other aliasCIS-4
SOCS-4
SOCS-6
HGNC (Hugo) SOCS6
LocusID (NCBI) 9306
Atlas_Id 42351
Location 18q22.2  [Link to chromosome band 18q22]
Location_base_pair Starts at 70288901 and ends at 70330198 bp from pter ( according to hg19-Feb_2009)  [Mapping SOCS6.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

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.

Protein

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

Note
  
Entity 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 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 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 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 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 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).
  

Bibliography

Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling.
Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P.
J Biol Chem. 2004 Mar 26;279(13):12249-59. Epub 2004 Jan 5.
PMID 14707129
 
The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins.
Bayle J, Lopez S, Iwai K, Dubreuil P, De Sepulveda P.
FEBS Lett. 2006 May 15;580(11):2609-14. Epub 2006 Apr 21.
PMID 16643902
 
The nuclear localization of SOCS6 requires the N-terminal region and negatively regulates Stat3 protein levels.
Hwang MN, Min CH, Kim HS, Lee H, Yoon KA, Park SY, Lee ES, Yoon S.
Biochem Biophys Res Commun. 2007 Aug 24;360(2):333-8. Epub 2007 Jun 19.
PMID 17603019
 
SOCS proteins in regulation of receptor tyrosine kinase signaling.
Kazi JU, Kabir NN, Flores-Morales A, Ronnstrand L.
Cell Mol Life Sci. 2014 Apr 5.
PMID 24705897
 
Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3.
Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, Ronnstrand L.
J Biol Chem. 2012 Oct 19;287(43):36509-17. doi: 10.1074/jbc.M112.376111. Epub 2012 Sep 5.
PMID 22952242
 
SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation.
Krebs DL, Uren RT, Metcalf D, Rakar S, Zhang JG, Starr R, De Souza DP, Hanzinikolas K, Eyles J, Connolly LM, Simpson RJ, Nicola NA, Nicholson SE, Baca M, Hilton DJ, Alexander WS.
Mol Cell Biol. 2002 Jul;22(13):4567-78.
PMID 12052866
 
SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation.
Lai RH, Hsiao YW, Wang MJ, Lin HY, Wu CW, Chi CW, Li AF, Jou YS, Chen JY.
Cancer Lett. 2010 Feb 1;288(1):75-85. doi: 10.1016/j.canlet.2009.06.025. Epub 2009 Jul 30.
PMID 19646809
 
Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation.
Lin HY, Lai RH, Lin ST, Lin RC, Wang MJ, Lin CC, Lee HC, Wang FF, Chen JY.
Cell Death Differ. 2013 Jan;20(1):139-53. doi: 10.1038/cdd.2012.106. Epub 2012 Sep 7.
PMID 22955947
 
Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance.
Mooney RA, Senn J, Cameron S, Inamdar N, Boivin LM, Shang Y, Furlanetto RW.
J Biol Chem. 2001 Jul 13;276(28):25889-93. Epub 2001 May 7.
PMID 11342531
 
Reduced expression of SOCS2 and SOCS6 in hepatocellular carcinoma correlates with aggressive tumor progression and poor prognosis.
Qiu X, Zheng J, Guo X, Gao X, Liu H, Tu Y, Zhang Y.
Mol Cell Biochem. 2013 Jun;378(1-2):99-106. doi: 10.1007/s11010-013-1599-5. Epub 2013 Mar 11.
PMID 23475171
 
Array-comParatyvå genomic hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma.
Sriram KB, Larsen JE, Savarimuthu Francis SM, Wright CM, Clarke BE, Duhig EE, Brown KM, Hayward NK, Yang IA, Bowman RV, Fong KM.
PLoS One. 2012;7(2):e30398. doi: 10.1371/journal.pone.0030398. Epub 2012 Feb 17.
PMID 22363434
 
MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer.
Wu K, Hu G, He X, Zhou P, Li J, He B, Sun W.
Pathol Oncol Res. 2013 Oct;19(4):739-48. doi: 10.1007/s12253-013-9637-x. Epub 2013 May 9.
PMID 23653113
 
Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase.
Zadjali F, Pike AC, Vesterlund M, Sun J, Wu C, Li SS, Ronnstrand L, Knapp S, Bullock AN, Flores-Morales A.
J Biol Chem. 2011 Jan 7;286(1):480-90. doi: 10.1074/jbc.M110.173526. Epub 2010 Oct 28.
PMID 21030588
 
Expression of SOCSs in human prostate cancer and their association in prognosis.
Zhu JG, Dai QS, Han ZD, He HC, Mo RJ, Chen G, Chen YF, Wu YD, Yang SB, Jiang FN, Chen WH, Sun ZL, Zhong WD.
Mol Cell Biochem. 2013 Sep;381(1-2):51-9. doi: 10.1007/s11010-013-1687-6. Epub 2013 May 11.
PMID 23666742
 

Citation

This paper should be referenced as such :
JU Kazi, A Flores-Morales, L Rè_nnstrand
SOCS6 (Suppressor Of Cytokine Signaling 6)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):50-52.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SOCS6ID42351ch18q22.html


External links

Nomenclature
HGNC (Hugo)SOCS6   16833
Cards
AtlasSOCS6ID42351ch18q22
Entrez_Gene (NCBI)SOCS6  9306  suppressor of cytokine signaling 6
AliasesCIS-4; CIS4; HSPC060; SOCS-4; 
SOCS-6; SOCS4; SSI4; STAI4; STATI4
GeneCards (Weizmann)SOCS6
Ensembl hg19 (Hinxton)ENSG00000170677 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000170677 [Gene_View]  chr18:70288901-70330198 [Contig_View]  SOCS6 [Vega]
ICGC DataPortalENSG00000170677
TCGA cBioPortalSOCS6
AceView (NCBI)SOCS6
Genatlas (Paris)SOCS6
WikiGenes9306
SOURCE (Princeton)SOCS6
Genetics Home Reference (NIH)SOCS6
Genomic and cartography
GoldenPath hg38 (UCSC)SOCS6  -     chr18:70288901-70330198 +  18q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SOCS6  -     18q22.2   [Description]    (hg19-Feb_2009)
EnsemblSOCS6 - 18q22.2 [CytoView hg19]  SOCS6 - 18q22.2 [CytoView hg38]
Mapping of homologs : NCBISOCS6 [Mapview hg19]  SOCS6 [Mapview hg38]
OMIM605118   
Gene and transcription
Genbank (Entrez)AB006968 AF161545 AK024356 BC020082
RefSeq transcript (Entrez)NM_004232
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SOCS6
Cluster EST : UnigeneHs.44439 [ NCBI ]
CGAP (NCI)Hs.44439
Alternative Splicing GalleryENSG00000170677
Gene ExpressionSOCS6 [ NCBI-GEO ]   SOCS6 [ EBI - ARRAY_EXPRESS ]   SOCS6 [ SEEK ]   SOCS6 [ MEM ]
Gene Expression Viewer (FireBrowse)SOCS6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9306
GTEX Portal (Tissue expression)SOCS6
Human Protein AtlasENSG00000170677-SOCS6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO14544   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO14544  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO14544
Splice isoforms : SwissVarO14544
PhosPhoSitePlusO14544
Domaine pattern : Prosite (Expaxy)SH2 (PS50001)    SOCS (PS50225)   
Domains : Interpro (EBI)SH2    SOCS6    SOCS_box   
Domain families : Pfam (Sanger)SH2 (PF00017)    SOCS_box (PF07525)   
Domain families : Pfam (NCBI)pfam00017    pfam07525   
Domain families : Smart (EMBL)SH2 (SM00252)  SOCS (SM00253)  SOCS_box (SM00969)  
Conserved Domain (NCBI)SOCS6
DMDM Disease mutations9306
Blocks (Seattle)SOCS6
PDB (SRS)2VIF   
PDB (PDBSum)2VIF   
PDB (IMB)2VIF   
PDB (RSDB)2VIF   
Structural Biology KnowledgeBase2VIF   
SCOP (Structural Classification of Proteins)2VIF   
CATH (Classification of proteins structures)2VIF   
SuperfamilyO14544
Human Protein Atlas [tissue]ENSG00000170677-SOCS6 [tissue]
Peptide AtlasO14544
HPRD05491
IPIIPI00297351   
Protein Interaction databases
DIP (DOE-UCLA)O14544
IntAct (EBI)O14544
FunCoupENSG00000170677
BioGRIDSOCS6
STRING (EMBL)SOCS6
ZODIACSOCS6
Ontologies - Pathways
QuickGOO14544
Ontology : AmiGOimmunological synapse  protein kinase inhibitor activity  protein binding  cytoplasm  negative regulation of protein kinase activity  defense response  JAK-STAT cascade  proteasomal protein catabolic process  protein ubiquitination  cytokine-mediated signaling pathway  regulation of growth  negative regulation of JAK-STAT cascade  negative regulation of T cell activation  
Ontology : EGO-EBIimmunological synapse  protein kinase inhibitor activity  protein binding  cytoplasm  negative regulation of protein kinase activity  defense response  JAK-STAT cascade  proteasomal protein catabolic process  protein ubiquitination  cytokine-mediated signaling pathway  regulation of growth  negative regulation of JAK-STAT cascade  negative regulation of T cell activation  
Pathways : KEGGProlactin signaling pathway   
REACTOMEO14544 [protein]
REACTOME PathwaysR-HSA-1433559 [pathway]   
NDEx NetworkSOCS6
Atlas of Cancer Signalling NetworkSOCS6
Wikipedia pathwaysSOCS6
Orthology - Evolution
OrthoDB9306
GeneTree (enSembl)ENSG00000170677
Phylogenetic Trees/Animal Genes : TreeFamSOCS6
HOVERGENO14544
HOGENOMO14544
Homologs : HomoloGeneSOCS6
Homology/Alignments : Family Browser (UCSC)SOCS6
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSOCS6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SOCS6
dbVarSOCS6
ClinVarSOCS6
1000_GenomesSOCS6 
Exome Variant ServerSOCS6
ExAC (Exome Aggregation Consortium)ENSG00000170677
GNOMAD BrowserENSG00000170677
Genetic variants : HAPMAP9306
Genomic Variants (DGV)SOCS6 [DGVbeta]
DECIPHERSOCS6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSOCS6 
Mutations
ICGC Data PortalSOCS6 
TCGA Data PortalSOCS6 
Broad Tumor PortalSOCS6
OASIS PortalSOCS6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSOCS6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSOCS6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SOCS6
DgiDB (Drug Gene Interaction Database)SOCS6
DoCM (Curated mutations)SOCS6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SOCS6 (select a term)
intoGenSOCS6
NCG5 (London)SOCS6
Cancer3DSOCS6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605118   
Orphanet
MedgenSOCS6
Genetic Testing Registry SOCS6
NextProtO14544 [Medical]
TSGene9306
GENETestsSOCS6
Target ValidationSOCS6
Huge Navigator SOCS6 [HugePedia]
snp3D : Map Gene to Disease9306
BioCentury BCIQSOCS6
ClinGenSOCS6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9306
Chemical/Pharm GKB GenePA134917653
Clinical trialSOCS6
Miscellaneous
canSAR (ICR)SOCS6 (select the gene name)
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSOCS6
EVEXSOCS6
GoPubMedSOCS6
iHOPSOCS6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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