SOCS6 (Suppressor Of Cytokine Signaling 6)

2014-05-01 Julhash U Kazi , Amilcar Flores-Morales , Lars Rönnstrand Affiliation

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)

Identity

HGNC

SOCS6

LOCATION

18q22.2

LOCUSID

9306

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).

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

Gene ID	Transcript ID	Uniprot
ENSG00000170677	ENST00000397942	O14544
ENSG00000170677	ENST00000397942	A0A024R379
ENSG00000170677	ENST00000578377	J3KTM7
ENSG00000170677	ENST00000582322	O14544
ENSG00000170677	ENST00000582322	A0A024R379

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Jak-STAT signaling pathway	KEGG	ko04630
Jak-STAT signaling pathway	KEGG	hsa04630
ECS complex	KEGG	hsa_M00388
ECS complex	KEGG	M00388
Prolactin signaling pathway	KEGG	hsa04917
Prolactin signaling pathway	KEGG	ko04917
JAK-STAT signaling	KEGG	hsa_M00684
JAK-STAT signaling	KEGG	M00684
Signal Transduction	REACTOME	R-HSA-162582
Signaling by SCF-KIT	REACTOME	R-HSA-1433557
Regulation of KIT signaling	REACTOME	R-HSA-1433559

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
23653113	2013	MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer.	41
19646809	2010	SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation.	27
21030588	2011	Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase.	24
24801601	2014	miR-17-5p promotes proliferation by targeting SOCS6 in gastric cancer cells.	24
22952242	2012	Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3.	23
22955947	2013	Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation.	22
23475171	2013	Reduced expression of SOCS2 and SOCS6 in hepatocellular carcinoma correlates with aggressive tumor progression and poor prognosis.	19
25025962	2014	Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer.	17

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