Reviewed, UniProtKB/Swiss-Prot O35718 (SOCS3_MOUSE)

Names and origin

Protein names

Recommended name:
    Suppressor of cytokine signaling 3
      Short name=SOCS-3
Alternative name(s):
    Cytokine-inducible SH2 protein 3
      Short name=CIS-3
    Protein EF-10

Gene names

Name:	Socs3
Synonyms:	Cis3, Cish3

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	225 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Inhibits cytokine signal transduction by binding to tyrosine kinase receptors including gp130, LIF, erythropoietin, insulin, IL12, GCSF and leptin receptors. Binding to JAK2 inhibits its kinase activity. Suppresses fetal liver erythropoiesis. Regulates onset and maintenance of allergic responses mediated by T-helper type 2 cells. Regulates IL-6 signaling in vivo. Probable substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins By similarity. Seems to recognize IL6ST. Ref.7 Ref.10 Ref.11 Ref.12
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts with multiple activated proteins of the tyrosine kinase signaling pathway including IGF1 receptor, insulin receptor and JAK2. Binding to JAK2 is mediated through the KIR and SH2 domains to a phosphorylated tyrosine residue within the JAK2 JH1 domain. Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors. Interaction with CSNK1E stabilizes SOCS3 protein. Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, elongin BC complex and SOCS3. Interacts with CUL5, RNF7, TCEB1 and TCEB2 By similarity. Ref.8
Tissue specificity	Low expression in lung, spleen and thymus. Expressed in Th2 but not TH1 cells. Ref.9
Developmental stage	In the developing brain, expressed at low levels from E10 stages to young adulthood (P25) with peak levels from E14 to P8. In the cortex, first expressed uniformly in all cells at E14. Not expressed in the retina. Highly expressed in fetal liver progenitors at E12.5.
Induction	By a subset of cytokines including EPO, leptin, LIF, IL-2, IL-3, IL-4, IGF1, growth hormone and prolactin. Ref.12
Domain	The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition. The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes By similarity.
Post-translational modification	Phosphorylated on tyrosine residues after stimulation by the cytokines, IL-2, EPO or IGF1 By similarity.
Sequence similarities	Contains 1 SH2 domain. Contains 1 SOCS box domain.

Ontologies

Keywords
Biological process	Growth regulation Ubl conjugation pathway
Domain	SH2 domain
Molecular function	Signal transduction inhibitor
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	branching involved in embryonic placenta morphogenesis Inferred from mutant phenotype. Source: MGI modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of insulin receptor signaling pathway Inferred from direct assay. Source: MGI placenta blood vessel development Inferred from mutant phenotype. Source: MGI positive regulation of cell differentiation Inferred from direct assay. Source: MGI regulation of growth Inferred from electronic annotation. Source: UniProtKB-KW regulation of protein amino acid phosphorylation Inferred from direct assay. Source: MGI spongiotrophoblast differentiation Inferred from genetic interaction. Source: MGI trophoblast giant cell differentiation Inferred from genetic interaction. Source: MGI
Molecular function	protein binding Inferred from physical interaction. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 225

225

Suppressor of cytokine signaling 3

PRO_0000181244

Regions

Domain

46 – 142

97

SH2

Domain

177 – 224

48

SOCS box

Region

22 – 33

12

Kinase inhibitory region (KIR)

Region

34 – 45

12

Extended SH2 subdomain (ESS)

Experimental info

Mutagenesis

22

1

L → A: No effect on LIF-induced signal transduction suppression. Ref.8

Mutagenesis

22

1

L → D: Abolishes binding to JAK2. No effect on binding to EPOR. Ref.8

Mutagenesis

25

1

F → A: Loss of LIF/EPO-induced signal transduction suppression. Abolishes binding to JAK2 and to EPOR. Ref.8

Mutagenesis

30

1

E → R: No effect on LIF-induced signal transduction suppression.

Mutagenesis

45

1

G → A: Abolishes binding to EPOR. No effect on binding to JAK2. Ref.8

Mutagenesis

71

1

R → K: Little effect on LIF-induced signal transduction suppression. Loss of EPO-induced signal transduction suppression. Abolishes binding to JAK2 and EPOR. Ref.8

Secondary structure

1

.

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225

Helix Strand Turn

Details...

Helix

32 – 43

12

Beta strand

45 – 48

4

Helix

53 – 61

9

Beta strand

67 – 72

6

Beta strand

79 – 86

8

Beta strand

89 – 96

8

Helix

98 – 100

3

Beta strand

102 – 104

3

Beta strand

117 – 119

3

Helix

120 – 126

7

Beta strand

165 – 167

3

Beta strand

174 – 176

3

Sequences

	Sequence		Length	Mass (Da)
	O35718-1 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: CD3859561D4CCDED	FASTA	225	24,776
	10 20 30 40 50 60 MVTHSKFPAA GMSRPLDTSL RLKTFSSKSE YQLVVNAVRK LQESGFYWSA VTGGEANLLL 70 80 90 100 110 120 SAEPAGTFLI RDSSDQRHFF TLSVKTQSGT KNLRIQCEGG SFSLQSDPRS TQPVPRFDCV 130 140 150 160 170 180 LKLVHHYMPP PGTPSFSLPP TEPSSEVPEQ PPAQALPGST PKRAYYIYSG GEKIPLVLSR 190 200 210 220 PLSSNVATLQ HLCRKTVNGH LDSYEKVTQL PGPIREFLDQ YDAPL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A family of cytokine-inducible inhibitors of signaling." Starr R., Willson T.A., Viney E.M., Murray L.J.L., Rayner J.R., Jenkins B.J., Gonda T.J., Alexander W.S., Metcalf D., Nicola N.A., Hilton D.J. Nature 387:917-921(1997) [PubMed: 9202125] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung and Thymus.
[2]	"Murine SOCS3 gene structure." Le Provost F., Henninghausen L. Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J and NOD. Tissue: Bone marrow, Cerebellum and Spleen.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6. Tissue: Brain.
[5]	"Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter." Auernhammer C.J., Bousquet C., Melmed S. Proc. Natl. Acad. Sci. U.S.A. 96:6964-6969(1999) [PubMed: 10359822] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30. Strain: ICR X Swiss Webster.
[6]	"E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3T3 fibroblasts." Fu X., Kamps M.P. Mol. Cell. Biol. 17:1503-1512(1997) [PubMed: 9032278] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 221-225. Strain: BALB/c.
[7]	"Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction." Nicholson S.E., Willson T.A., Farley A., Starr R., Zhang J.-G., Baca M., Alexander W.S., Metcalf D., Hilton D.J., Nicola N.A. EMBO J. 18:375-385(1999) [PubMed: 9889194] [Abstract] Cited for: FUNCTION IN LIF AND IL6 SIGNALING.
[8]	"CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2." Sasaki A., Yasukawa H., Shouda T., Kitamura T., Dikic I., Yoshimura A. J. Biol. Chem. 275:29338-29347(2000) [PubMed: 10882725] [Abstract] Cited for: INTERACTION WITH EPOR AND JAK2, MUTAGENESIS OF LEU-22; PHE-25; GLY-45 AND ARG-71.
[9]	"Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation." Seki Y., Hayashi K., Matsumoto A., Seki N., Tsukada J., Ransom J., Naka T., Kishimoto T., Yoshimura A., Kubo M. Proc. Natl. Acad. Sci. U.S.A. 99:13003-13008(2002) [PubMed: 12242343] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"SOCS3 is essential in the regulation of fetal liver erythropoiesis." Marine J.-C., McKay C., Wang D., Topham D.J., Parganas E., Nakajima H., Pendeville H., Yasukawa H., Sasaki A., Yoshimura A., Ihle J.N. Cell 98:617-627(1999) [PubMed: 10490101] [Abstract] Cited for: FUNCTION IN ERYTHROPOIESIS.
[11]	"SOCS3 negatively regulates IL-6 signaling in vivo." Croker B.A., Krebs D.L., Zhang J.-G., Wormald S., Willson T.A., Stanley E.G., Robb L., Greenhalgh C.J., Foerster I., Clausen B.E., Nicola N.A., Metcalf D., Hilton D.J., Roberts A.W., Alexander W.S. Nat. Immunol. 4:540-545(2003) [PubMed: 12754505] [Abstract] Cited for: ROLE IN IL-6 SIGNALING.
[12]	"SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses." Seki Y., Inoue H., Nagata N., Hayashi K., Fukuyama S., Matsumoto K., Komine O., Hamano S., Himeno K., Inagaki-Ohara K., Cacalano N., O'Garra A., Oshida T., Saito H., Johnston J.A., Yoshimura A., Kubo M. Nat. Med. 9:1047-1054(2003) [PubMed: 12847520] [Abstract] Cited for: ROLE IN ALLERGIC RESPONSE, INDUCTION BY IL-4.
[13]	"The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability." Babon J.J., McManus E.J., Yao S., DeSouza D.P., Mielke L.A., Sprigg N.S., Willson T.A., Hilton D.J., Nicola N.A., Baca M., Nicholson S.E., Norton R.S. Mol. Cell 22:205-216(2006) [PubMed: 16630890] [Abstract] Cited for: STRUCTURE BY NMR OF 22-185.
[14]	"Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3." Bergamin E., Wu J., Hubbard S.R. Structure 14:1285-1292(2006) [PubMed: 16905102] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 15-185 IN COMPLEX WITH PHOSPHORYLATED IL6ST.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U88328 mRNA. Translation: AAB62403.1.
AF314501 Genomic DNA. Translation: AAK60601.1.
AK047165 mRNA. Translation: BAC32977.1.
AK139241 mRNA. Translation: BAE23929.1.
AK152468 mRNA. Translation: BAE31244.1.
AK152514 mRNA. Translation: BAE31277.1.
AK157708 mRNA. Translation: BAE34161.1.
AK159395 mRNA. Translation: BAE35049.1.
AK170406 mRNA. Translation: BAE41773.1.
AK172399 mRNA. Translation: BAE42985.1.
BC052031 mRNA. Translation: AAH52031.1.
AF117732 Genomic DNA. Translation: AAD18024.1.
U72673 mRNA. Translation: AAB51035.1. Sequence problems.

IPI

IPI00133840.

RefSeq

NP_031733.1.

UniGene

Mm.3468

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2BBU	NMR	-	A	22-185	[»]
2HMH	X-ray	2.00	A	15-185	[»]
2JZ3	NMR	-	A	186-225	[»]

SMR

O35718. Positions 33-222.

DisProt

DP00446.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29137N.

STRING

O35718.

PTM databases

PhosphoSite

O35718.

Proteomic databases

PRIDE

O35718.

Genome annotation databases

Ensembl

ENSMUST00000054002; ENSMUSP00000059129; ENSMUSG00000053113; Mus musculus. [Genome view]

GeneID

12702.

KEGG

mmu:12702.

UCSC

uc007moi.1. mouse.

Organism-specific databases

CTD

12702.

MGI

MGI:1201791. Socs3.

Phylogenomic databases

eggNOG

roNOG14048.

HOGENOM

HBG715092.

HOVERGEN

O35718.

InParanoid

O35718.

OMA

GFYWSTV.

OrthoDB

EOG9258D3.

PhylomeDB

O35718.

Gene expression databases

ArrayExpress

O35718.

Bgee

O35718.

CleanEx

MM_SOCS3.

Genevestigator

O35718.

GermOnline

ENSMUSG00000053113. Mus musculus.

Family and domain databases

InterPro

IPR000980. SH2.
IPR001496. SOCS_C.
[Graphical view]

Gene3D

G3DSA:3.30.505.10. SH2. 1 hit.

Pfam

PF00017. SH2. 1 hit.
PF07525. SOCS_box. 1 hit.
[Graphical view]

SMART

SM00252. SH2. 1 hit.
SM00253. SOCS. 1 hit.
[Graphical view]

PROSITE

PS50001. SH2. 1 hit.
PS50225. SOCS. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

281958.

SOURCE

Search...

Entry information

Entry name

SOCS3_MOUSE

Accession

Primary (citable) accession number: O35718
Secondary accession number(s): P97803, Q3U7X5

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 16, 2002
Last sequence update:	January 1, 1998
Last modified:	January 19, 2010
This is version 89 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)