O35716 (SOCS1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Suppressor of cytokine signaling 1
Short name=SOCS-1

Alternative name(s):
JAK-binding protein
Short name=JAB
STAT-induced STAT inhibitor 1
Short name=SSI-1

Gene names

Name:	Socs1
Synonyms:	Cish1, Ssi1

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 › Mus

Protein attributes

Sequence length	212 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. SOCS1 is involved in negative regulation of cytokines that signal through the JAK/STAT3 pathway. Through binding to JAKs, inhibits their kinase activity. In vitro, also suppresses Tec protein-tyrosine activity By similarity. Appears to be a major regulator of signaling by interleukin 6 (IL6) and leukemia inhibitory factor (LIF). Regulates interferon-gamma mediated sensory neuron survival. Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Seems to recognize JAK2 By similarity. Ref.14
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts with multiple activated proteins of the tyrosine kinase signaling pathway including JAK family kinases, TEC, KIT, GRB2 and VAV. Binding to JAKs is mediated through the KIR and SH2 domain to a phosphorylated tyrosine residue within the JAK JH1 domain. Binds the SH3 domain of GRB2 via diproline determinants in the N-terminus, and the N-terminal regulatory domain of VAV. Interacts with the Elongin BC complex (TCEB1 and TCEB2). Component of an ECS CBC(SOCS1) E3 ubiquitin-protein ligase complex which contains Elongin BC, CUL5, RBX1 and SOCS1. Interacts (via SH2 domain and SOCS box) with TRIM8. Interacts with CUL2. Interacts with AXL and FGFR3 By similarity. Interacts with INSR. Ref.8 Ref.9 Ref.10
Subcellular location	Nucleus By similarity. Cytoplasmic vesicle By similarity. Note: Detected in perinuclear cytoplasmic vesicles upon interaction with FGFR3 By similarity.
Tissue specificity	High expression in thymus. Lower expression in lung and spleen. Expressed in both Th1 and Th2 cells. Ref.16
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, expression first observed at E14 uniformly in all cells. Also expressed in the innermost layers of the developing retina. Levels of expression remain unchanged from P8 until adulthood. In the peripheral nervous system, high levels found in virtually all neurons of the dorsal root ganglion.
Induction	By a subset of cytokines including those belonging to the interferon, interleukin and colony-stimulating factor families.
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. The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV] and is part of the SOCS box.
Disruption phenotype	Mice exhibit lymphocyte deficiency and degeneration of the liver parenchyma. Animals die within 3 weeks of age. Ref.12
Sequence similarities	Contains 1 SH2 domain. Contains 1 SOCS box domain.

Ontologies

Keywords
Biological process	Growth regulation Ubl conjugation pathway
Cellular component	Cytoplasmic vesicle Nucleus
Domain	SH2 domain
Molecular function	Signal transduction inhibitor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	JAK-STAT cascade Inferred from direct assay. Source: MGI cellular response to amino acid stimulus Inferred from direct assay. Source: MGI cytokine-mediated signaling pathway Inferred from direct assay Ref.2Ref.3. Source: MGI fat cell differentiation Inferred from mutant phenotype. Source: MGI negative regulation of insulin receptor signaling pathway Inferred from direct assay Ref.17. Source: MGI negative regulation of tyrosine phosphorylation of Stat3 protein Inferred from direct assay Ref.3. Source: MGI regulation of growth Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasmic membrane-bounded vesicle Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Traceable author statement. Source: Reactome nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	kinase inhibitor activity Inferred from direct assay Ref.2Ref.13. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 212	212	Suppressor of cytokine signaling 1		PRO_0000181236
Regions
	Domain	80 – 175	96	SH2
	Domain	162 – 211	50	SOCS box
	Region	56 – 67	12	Kinase inhibitory region (KIR)
	Region	68 – 79	12	Extended SH2 subdomain (ESS)
	Region	174 – 183	10	Interaction with Elongin BC complex
	Compositional bias	26 – 33	8	Poly-Ser
Experimental info
	Mutagenesis	51	1	P → A: No effect on LIF signal transduction suppression.
	Mutagenesis	52	1	G → A: No effect on LIF signal transduction suppression.
	Mutagenesis	53	1	D → A or R: No effect on LIF signal transduction suppression.
	Mutagenesis	54	1	T → A: No effect on LIF signal transduction suppression.
	Mutagenesis	55	1	H → A or D: No effect on JAK signal transduction suppression. Ref.14
	Mutagenesis	56	1	F → A, S or D: Loss of JAK signal transduction suppression. Ref.14
	Mutagenesis	56	1	F → E or S: Reduced binding to JH1. Ref.14
	Mutagenesis	56	1	F → L: No effect on JAK signal transduction inhibition nor on binding to JH1. Ref.14
	Mutagenesis	57	1	R → A or E: No effect on JAK signal transduction suppression. Ref.14
	Mutagenesis	58	1	T → A: No effect on JAK signal transduction suppression. Ref.14
	Mutagenesis	59	1	F → A or E: Loss of JAK signal transduction suppression. Reduced binding to JH1. Ref.14 Ref.15
	Mutagenesis	59	1	F → D: Loss of JAK signal transduction suppression. Destabilization of SOCS1. Ref.14 Ref.15
	Mutagenesis	59	1	F → L: No effect on JAK signal transduction suppression nor on binding to JH1. Ref.14 Ref.15
	Mutagenesis	60	1	R → A: No effect on LIF signal transduction suppression. Ref.14
	Mutagenesis	61	1	S → E: No effect on JAK signal transduction suppression. Ref.14
	Mutagenesis	62	1	H → E: No effect on JAK signal transduction suppression. Ref.14
	Mutagenesis	64	1	D → R: Loss of JAK signal transduction suppression. Reduced binding to JH1. Ref.14
	Mutagenesis	65	1	Y → A: Some loss of JAK signal transduction signaling. Reduced binding to JH1. Ref.14
	Mutagenesis	68	1	I → E: Loss of binding to JH1/Y-1007 of JAK2 and loss of signal transduction suppression.
	Mutagenesis	70	1	R → E: No effect on LIF signal transduction suppression.
	Mutagenesis	75	1	L → E: Loss of binding to JH1/Y-1007 of JAK2 and loss of signal transduction suppression.
	Mutagenesis	105	1	R → K: Loss of LIF signal transduction suppression. Loss of binding to KIT. No effect on binding to VAV. Ref.14
	Mutagenesis	105	1	R → Q: Loss of IL-6 signal transduction suppression. No effect on binding to TYK2. Ref.14
	Mutagenesis	175	1	L → P: Abolishes interaction with elongin BC complex; when associated with F-179. Ref.8
	Mutagenesis	179	1	C → F: Abolishes interaction with elongin BC complex; when associated with P-175. Ref.8
	Sequence conflict	141	1	S → N in BAA21538. Ref.2
	Sequence conflict	141	1	S → N in BAA21539. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	O35716 [UniParc]. Last modified January 1, 1998. Version 1. Checksum: 4621E05DC3D44C69	FASTA	212	23,715
	10 20 30 40 50 60 MVARNQVAAD NAISPAAEPR RRSEPSSSSS SSSPAAPVRP RPCPAVPAPA PGDTHFRTFR 70 80 90 100 110 120 SHSDYRRITR TSALLDACGF YWGPLSVHGA HERLRAEPVG TFLVRDSRQR NCFFALSVKM 130 140 150 160 170 180 ASGPTSIRVH FQAGRFHLDG SRETFDCLFE LLEHYVAAPR RMLGAPLRQR RVRPLQELCR 190 200 210 QRIVAAVGRE NLARIPLNPV LRDYLSSFPF QI

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: Thymus.
[2]	"A new protein containing an SH2 domain that inhibits JAK kinases." Endo T.A., Masuhara M., Yokouchi M., Suzuki R., Sakamoto H., Mitsui K., Matsumoto A., Tanimura S., Ohtsubo M., Misawa H., Miyazaki T., Leonor N., Taniguchi T., Fujita T., Kanakura Y., Komiya S., Yoshimura A. Nature 387:921-924(1997) [PubMed: 9202126] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Structure and function of a new STAT-induced STAT inhibitor." Naka T., Narazaki M., Hirata M., Matsumoto T., Minamoto S., Aono A., Nishimoto N., Kajita T., Taga T., Yoshizaki K., Akira S., Kishimoto T. Nature 387:924-929(1997) [PubMed: 9202127] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Thymus.
[4]	"SOCS-1 binds to multiple signaling proteins and suppresses Steel factor-dependent proliferation." De Sepulveda P., Okkenhaug K., La Rose J., Hawley R.G., Dubreuil P., Rottapel R. EMBO J. 18:904-915(1999) [PubMed: 10022833] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Hematopoietic.
[5]	"Regulation of SOCS-1 expression by translational repression." Gregorieff A., Pyronnet S., Sonenberg N., Veillette A. J. Biol. Chem. 275:21596-21604(2000) [PubMed: 10764816] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"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: Skin.
[7]	"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]. Tissue: Lung.
[8]	"The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families." Kamura T., Sato S., Haque D., Liu L., Kaelin W.G. Jr., Conaway R.C., Conaway J.W. Genes Dev. 12:3872-3881(1998) [PubMed: 9869640] [Abstract] Cited for: INTERACTION WITH ELONGIN BC COMPLEX, MUTAGENESIS OF LEU-175 AND CYS-179.
[9]	"The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation." Zhang J.-G., Farley A., Nicholson S.E., Willson T.A., Zugaro L.M., Simpson R.J., Moritz R.L., Cary D., Richardson R., Hausmann G., Kile B.J., Kent S.B.H., Alexander W.S., Metcalf D., Hilton D.J., Nicola N.A., Baca M. Proc. Natl. Acad. Sci. U.S.A. 96:2071-2076(1999) [PubMed: 10051596] [Abstract] Cited for: INTERACTION WITH ELONGIN BC COMPLEX.
[10]	"TRIM8/GERP RING finger protein interacts with SOCS-1." Toniato E., Chen X.P., Losman J., Flati V., Donahue L., Rothman P. J. Biol. Chem. 277:37315-37322(2002) [PubMed: 12163497] [Abstract] Cited for: INTERACTION WITH TRIM8.
[11]	"Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling." Narazaki M., Fujimoto M., Matsumoto T., Morita Y., Saito H., Kajita T., Yoshizaki K., Naka T., Kishimoto T. Proc. Natl. Acad. Sci. U.S.A. 95:13130-13134(1998) [PubMed: 9789053] [Abstract] Cited for: MUTAGENESIS.
[12]	"Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1." Starr R., Metcalf D., Elefanty A.G., Brysha M., Willson T.A., Nicola N.A., Hilton D.J., Alexander W.S. Proc. Natl. Acad. Sci. U.S.A. 95:14395-14399(1998) [PubMed: 9826711] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[13]	"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: MUTAGENESIS.
[14]	"The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop." Yasukawa H., Misawa H., Sakamoto H., Masuhara M., Sasaki A., Wakioka T., Ohtsuka S., Imaizumi T., Matsuda T., Ihle J.N., Yoshimura A. EMBO J. 18:1309-1320(1999) [PubMed: 10064597] [Abstract] Cited for: FUNCTION IN INHIBITION OF JAK2 KINASE ACTIVITY, MUTAGENESIS OF HIS-55; PHE-56; ARG-57; THR-58; PHE-59; ARG-60; SER-61; HIS-62; ASP-64; TYR-65 AND ARG-105.
[15]	"A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box." Hanada T., Yoshida T., Kinjyo I., Minoguchi S., Yasukawa H., Kato S., Mimata H., Nomura Y., Seki Y., Kubo M., Yoshimura A. J. Biol. Chem. 276:40746-40754(2001) [PubMed: 11522790] [Abstract] Cited for: MUTAGENESIS OF PHE-59.
[16]	"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.
[17]	"Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms." Ueki K., Kondo T., Kahn C.R. Mol. Cell. Biol. 24:5434-5446(2004) [PubMed: 15169905] [Abstract] Cited for: FUNCTION IN INHIBITION OF INSR KINASE ACTIVITY, INTERACTION WITH INSR.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U88325 mRNA. Translation: AAB62400.1. AB000677 mRNA. Translation: BAA21538.1. AB000710 mRNA. Translation: BAA21539.1. AF120490 mRNA. Translation: AAD24777.1. AF180302 mRNA. Translation: AAD53324.1. AK028632 mRNA. Translation: BAC26040.1. AK154706 mRNA. Translation: BAE32775.1. BC132366 mRNA. Translation: AAI32367.1. BC132368 mRNA. Translation: AAI32369.1.
IPI	IPI00133836.
RefSeq	NP_034026.1. NM_009896.2.
UniGene	Mm.130.
3D structure databases
ProteinModelPortal	O35716.
SMR	O35716. Positions 64-212.
ModBase	Search...
Protein-protein interaction databases
IntAct	O35716. 4 interactions.
STRING	O35716.
Proteomic databases
PRIDE	O35716.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000038099; ENSMUSP00000038121; ENSMUSG00000038037.
GeneID	12703.
KEGG	mmu:12703.
UCSC	uc007yed.1. mouse.
Organism-specific databases
CTD	8651.
MGI	MGI:1354910. Socs1.
Phylogenomic databases
GeneTree	ENSGT00550000074283.
HOGENOM	HBG715092.
HOVERGEN	HBG002457.
InParanoid	O35716.
OMA	NCFFAIS.
OrthoDB	EOG4R7VC2.
PhylomeDB	O35716.
Gene expression databases
ArrayExpress	O35716.
Bgee	O35716.
CleanEx	MM_SOCS1.
Genevestigator	O35716.
GermOnline	ENSMUSG00000038037. Mus musculus.
Family and domain databases
InterPro	IPR000980. SH2. IPR001496. SOCS_C. [Graphical view]
Gene3D	G3DSA:3.30.505.10. SH2. 1 hit.
KO	K04694.
Pfam	PF00017. SH2. 1 hit. PF07525. SOCS_box. 1 hit. [Graphical view]
SMART	SM00252. SH2. 1 hit. SM00253. SOCS. 1 hit. SM00969. SOCS_box. 1 hit. [Graphical view]
PROSITE	PS50001. SH2. 1 hit. PS50225. SOCS. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	281962.
SOURCE	Search...

Entry information

Entry name

SOCS1_MOUSE

Accession

Primary (citable) accession number: O35716
Secondary accession number(s): A2RT46, O35960, Q3U3L0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 16, 2002
Last sequence update:	January 1, 1998
Last modified:	January 25, 2012
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program